JP5048448B2 - Method for purifying trans-(−)-Δ9-tetrahydrocannabinol and trans-(+)-Δ9-tetrahydrocannabinol - Google Patents

Abstract

Methods for making trans-(-)-” 9 -tetrahydrocannabinol and trans-(+)-” 9 -tetrahydrocannabinol are disclosed herein. In one embodiment, a trans-(-)-” 9 -tetrahydrocannabinol composition is prepared by allowing a composition comprising (±)-” 9 -tetrahydrocannabinol to separate on a chiral stationary phase to provide a trans-(-)-” 9 -tetrahydrocannabinol composition comprising at least about 99% by weight of trans-(-)-” 9 -tetrahydrocannabinol based on the total amount of trans-(-)-” 9 -tetrahydrocannabinol and trans-(+)-” 9 -tetrahydrocannabinol. The invention also relates to methods for treating or preventing a condition such as pain comprising administering to a patient in need thereof an effective amount of a trans-(-)-” 9 -tetrahydrocannabinol having a purity of at least about 98% based on the total weight of cannabinoids.

Description

The present invention relates to trans-(−)-Δ ⁹ -tetrahydrocannabinol or trans- (
+) -Δ ⁹ -tetrahydrocannabinol purification method; purified form of trans-(-
) - [delta ⁹ - tetrahydrocannabinol or trans - (+) - delta ⁹ - compositions comprising -tetrahydrocannabinol; and its necessary purified to a patient in the form of trans - (-
) -Δ ⁹ -Tetrahydrocannabinol. A method for treating or preventing a condition such as pain, vomiting, anorexia or weight loss.

(−)-6a, 10a-trans-Δ ⁹ -tetrahydrocannabinol (“(−)-Δ ⁹
-THC ") is a major cause of antiemetic effects associated with cannabis (SE Sallen et al., N. Engl
J. Med. 302: 135 (1980); AE Chang et al., Cancer 47: 1746 (1981); and DS
Poster et al., J. Am. Med. Asso. 245: 2047 (1981)). Trans-(-)-Δ ⁹ -TH
Both C and trans-(+)-Δ ⁹ -THC [trans-(−)-and (+)-enantiomers of (±) -Δ ⁹ -THC, respectively] are useful for treating pain It is reported that trans-(−)-Δ ⁹ -THC is trans-(+)-Δ ⁹ -THC.
Have been reported to be more potent (eg G. Jones et al., Biochem. Pharmacol. 23:
439 (1974); SH Roth, Can. J. Physiol. Pharmacol. 56: 968 (1978); BR Martin
et al., Life Sciences 29: 565 (1981); M. Reichman et al., Mol. Pharmacol. 34: 823
(1988); and M. Reichman et al., Mol. Pharmacol. 40: 547 (1991)). Trans-(−)-Δ ⁹ -THC is useful for reducing nausea and vomiting in patients undergoing cancer chemotherapy and for inducing weight gain in patients suffering from symptomatic HIV infection. It is reported to be an antiemetic (Plasse US Pat. No. 6,703,418 B)
2). Capsule formulations of synthetic trans-(−)-Δ ⁹ -THC in sesame oil (“dronabinol”) are available in Unim at 2.5, 5 and 10 mg dosage strengths.
ed Pharmaceuticals, Inc. From Marinol (registered trademark).

Trans-(−)-Δ ⁹ -THC can be extracted from hashish (Y. Gaoni et al.
al., J. Am. Chem. Soc. 93: 217 (1971); and Elsohly et al., US Pat. No. 6,3.
65,416 B1). However, the concentration of trans-(−)-Δ ⁹ -THC in the hashish is only in the range of about 1-5%, depending on its source, and even after extraction, trans-(−)-Δ ⁹ − THC must be separated from other impurities such as cannabinoid isomers.

RF Turk et al., J. Pharm. Pharmac. 23: 190-195 (1971) describes a method for the isolation of trans-(−)-Δ ⁹ -THC from marijuana. Contained unquantified THC carboxylic acid precursor.

The following paragraphs relate to known methods having the gist of producing trans-(−)-Δ ⁹ -THC or (±) -Δ ⁹ -THC.

Petrizilka U.S. Pat. No. 3,560,528 includes (−)-Δ ⁸ -THC.
P-toluenesulfonic acid monohydrate (“PTSA” in refluxing benzene to produce
H ₂ O ”) or the reaction of (+)-p-menta-2,8-dien-1-ol with olivetol in the presence of trifluoroacetic acid, this (−) — Δ ⁸ −
THC can be converted to trans-(−)-Δ ⁹ -THC by addition of HCl followed by dehydrochlorination.
(Y. Mechoulam et al., J. Am. Chem. Soc. 89: 4553 (1967)
And R. Mechoulam et al., J. Am. Chem. Soc. 94: 6159 (1972)).

US Pat. No. 4,025,516 to Razdan et al. Describes trans-(−)-Δ ⁹ -T.
Mixture of cis / trans-(+)-p-menta-2,8-dien-1-ol in the presence of excess non-alkaline dehydrating agent and acid catalyst in an inert organic solvent to form HC Is described in this patent, which includes trans-(−)-Δ ⁹ -THC.
(-)-Cannabidiol ("(-) under anhydrous conditions in an inert solvent to form
-CBD ") or (-) - abnormal -CBD (" (-) - abn-CBD ") with a Lewis acid, for example also the reaction with boron trifluoride diethyl ether (" BF ₃ · Et ₂ O ") is described ing.

RK Razdan et al., J. Am. Chem. Soc. 96: 5860 (1974) includes trans-(-)-
Cis / trans-(+)-p-menta-2,8-diene-1- in the presence of 1% BF ₃ .Et ₂ O, methylene chloride and anhydrous magnesium sulfate to form Δ ⁹ -THC The reaction of a mixture of oars with olivetol is described.

Olsen et al., US Pat. No. 4,381,399, describes a method for separating trans-(−)-Δ ⁹ -THC from a crude synthesis mixture, which comprises esterification of the crude mixture, Isolation of the resulting trans-(−)-Δ ⁹ -THC ester, hydrolysis of the ester, and distillation of trans-(−)-Δ ⁹ -THC under reduced pressure.

KE Fahrenholtz et al., J. Am. Chem. Soc. 89: 5934-5941 (1967) includes (±) −
(±) -1-m- with NaOH in aqueous methanol to produce Δ ⁹ -THC
The hydrolysis of nitrobenzenesulfonate-6a, 10a-trans-Δ ⁹ -tetrahydrocannabinol has been described, and its (±) -Δ ⁹ -THC is then crystallized from hexane.

EG Taylor et al., J. Am. Chem. Soc. 88: 367 (1966) includes (±) -Δ ⁹ -THC.
The reaction of citral and olivetol in acidified ethanol is described to form about 35% yield.

SL Levin et al., J. Chromatogr. A 654: 53-64 (1993) includes trans-(-)-
A method has been described for separating Δ ⁹ -THC and trans-(+)-Δ ⁹ -THC from compositions containing equimolar amounts of trans-(−)-and (+)-enantiomers.

Despite these described methods, there remains a need for improved methods for producing trans-(−)-Δ ⁹ -THC in pure or substantially pure form.

Citation of any reference in Section 2 of this application is not an admission that the reference is prior art to the application.

The present invention relates to a method for preparing a composition comprising trans-(−)-Δ ⁹ -THC or trans-(+)-Δ ⁹ -THC.

In one embodiment, the present invention provides at least about 98 based on the total amount of cannabinoids.
It relates to a process for the preparation of a composition comprising% by weight of trans-(−)-Δ ⁹ -THC.

In other embodiments, the present invention provides that a composition comprising (±) -Δ ⁹ -THC and an elution solvent is separated on a chiral stationary phase, resulting in a trans-(−)-Δ ⁹ -THC composition. comprising trans - (-) - relates to a process for the preparation of a composition comprising a delta ⁹ -THC, wherein the (±) - [delta ⁹
-THC is obtained from crystalline (±) -Δ ⁹ -THC.

In another embodiment, the present invention provides a composition comprising (±) -Δ ⁹ -THC and an eluting solvent separated on a chiral stationary phase to produce trans-(−)-Δ ⁹ -THC and trans-(+)
At least about 98% by weight of trans-(−)-Δ ⁹ -T, based on the total amount of -Δ ⁹ -THC.
Trans-(-comprising providing a trans-(−)-Δ ⁹ -THC composition comprising HC
−) − Δ ⁹ -THC The preparation method of the (±) -Δ ⁹ -THC is trans- (
-) - Δ ⁹ -THC, trans - (+) - Δ ⁹ -THC and a non-polar organic solvents from a first composition comprising trans a - (-) - Δ ⁹ -THC and trans - (+) - Δ ⁹ - THC was obtained by crystallizing out to give crystalline (±) -Δ ⁹ -THC and a liquid phase.

The present invention provides at least about 98% by weight of trans- (based on the total amount of cannabinoids.
It also relates to a process for preparing a composition comprising +)-Δ ⁹ -THC.

In one embodiment, the present invention includes separating a composition comprising (±) -Δ ⁹ -THC and an elution solvent with chiral immobilization to provide a trans-(+)-Δ ⁹ -THC composition. , Trans-(+)-Δ ⁹ -THC also relates to a method for preparing a composition comprising (±) -Δ ⁹
-THC is obtained from crystalline (±) -Δ ⁹ -THC.

In another embodiment, the present invention provides a composition comprising (±) -Δ ⁹ -THC and an eluting solvent separated on a chiral stationary phase to produce trans-(+)-Δ ⁹ -THC and trans-(-).
At least about 98% by weight of trans-(+)-Δ ⁹ -T, based on the total amount of -Δ ⁹ -THC.
Trans- () comprising providing a trans-(+)-Δ ⁹ -THC composition comprising HC
+)-Δ ⁹ -THC relates to a method for producing a composition, wherein the (±) -Δ ⁹ -THC is trans- (
-) - Δ ⁹ -THC, trans - (+) - Δ ⁹ -THC and a non-polar organic solvents from a first composition comprising trans a - (-) - Δ ⁹ -THC and trans - (+) - Δ ⁹ - THC was obtained by crystallizing out to give crystalline (±) -Δ ⁹ -THC and a liquid phase.

The present invention also relates to compositions comprising either trans-(−)-Δ ⁹ -THC or trans-(+)-Δ ⁹ -THC.

In one embodiment, the invention provides at least 99.0 based on the total amount of cannabinoids.
It relates to a composition comprising 0% by weight of trans-(−)-Δ ⁹ -THC.

In other embodiments, the invention provides at least 99 based on the total amount of cannabinoids.
. It relates to a composition comprising 0% by weight of trans-(+)-Δ ⁹ -THC.

The invention also relates to a pharmaceutical composition comprising trans-(−)-Δ ⁹ -THC. In one embodiment, the invention relates to a pharmaceutical composition comprising at least 99.0% by weight of trans-(−)-Δ ⁹ -THC based on the total amount of cannabinoids.

Furthermore, the present invention relates to a method for preventing or treating conditions such as vomiting, weight loss or anorexia, said method comprising at least 99.0% by weight, based on the total amount of cannabinoids, in need thereof. Administering an effective amount of a composition comprising% trans-(−)-Δ ⁹ -THC.

The invention can be more fully understood by reference to the following detailed description and illustrative examples, which are intended to exemplify non-limiting embodiments of the invention.

の構造を有する。
トランス−（＋）−Δ⁹−ＴＨＣは、（１ｂ）：

の構造を有する。 4.1. Definitions As used herein, the generic name “Δ ⁹ -THC” refers to trans-(−)-Δ ⁹ -THC,
Refers to trans-(+)-Δ ⁹ -THC, (±) -Δ ⁹ -THC, or any mixture thereof.
Trans-(−)-Δ ⁹ -THC has the formula (1a):

It has the structure of.
Trans-(+)-Δ ⁹ -THC is (1b):

It has the structure of.

の構造を有する。
（＋）−Δ⁸−ＴＨＣは、（２ｂ）：

の構造を有する。 As used herein, the generic name “Δ ⁸ -THC” is (−) − Δ ⁸ −THC, (+) − Δ.
^It refers to ^8- THC, (±) -Δ ⁸ -THC, or any mixture thereof.
(−) − Δ ⁸ −THC is represented by the formula (2a):

It has the structure of.
(+)-Δ ⁸ -THC is (2b):

It has the structure of.

の構造を有する。
（＋）−ＣＢＤは、式（３ｂ）：

の構造を有する。 As used herein, the generic name “CBD” is (−)-CBD, (+)-CBD, (±
) -CBD, or any mixture thereof.
(−)-CBD has the formula (3a):

It has the structure of.
(+)-CBD has the formula (3b):

It has the structure of.

（式中、Ｒは、−Ｃ（Ｏ）（３，５−Ｃ₆Ｈ₃（ＮＯ₂）₂である）
の構造を有する。
（＋）−ＣＢＤ−ビス（３，５−ジニトロベンゾエート）は、式（４ｂ）：

（式中、Ｒは、−Ｃ（Ｏ）（３，５−Ｃ₆Ｈ₃（ＮＯ₂）₂である）
の構造を有する。 As used herein, the generic name “CBD-bis-1,3- (3,5-dinitrobenzoate)” refers to (−)-CBD-bis (3,5-dinitrobenzoate), (+)-CBD.
-Refers to bis (3,5-dinitrobenzoate), (±) -CBD-bis (3,5-dinitrobenzoate), or any mixture thereof.
(−)-CBD-bis (3,5-dinitrobenzoate) has the formula (4a):

(In the formula, R is —C (O) (3,5-C ₆ H ₃ (NO ₂ ) ₂ )).
It has the structure of.
(+)-CBD-bis (3,5-dinitrobenzoate) has the formula (4b):

(In the formula, R is —C (O) (3,5-C ₆ H ₃ (NO ₂ ) ₂ )).
It has the structure of.

の構造を有し、
トランス−（＋）−Δ⁹−ＴＨＣカルボン酸は、式（５ｂ）：

の構造を有する。 As used herein, the generic name “trans-Δ ⁹ -THC carboxylic acid” refers to trans-
Refers to (−)-Δ ⁹ -THC carboxylic acid, trans-(+)-Δ ⁹ -THC carboxylic acid, trans- (±) -Δ ⁹ -THC carboxylic acid, or any mixture thereof,
Trans-(−)-Δ ⁹ -THC carboxylic acid has the formula (5a):

Having the structure of
Trans-(+)-Δ ⁹ -THC carboxylic acid has the formula (5b):

It has the structure of.

  The term “halide” refers to fluoride, chloride, bromide or iodide.

  The term “—halo” means —F, —Cl, —Br or —I.

The term “— (C ₁ -C ₄ ) alkyl” means a saturated straight or branched chain hydrocarbon having from 1 to 4 carbon atoms. Representative saturated straight chain (C ₁ -C ₄ ) alkyl are -methyl, -ethyl, -n-propyl and -n-butyl. Representative saturated branched - (C ₁ ~C ₄₎ alkyl, - isopropyl,-sec-butyl, - isobutyl and -tert- butyl.

The phrase “anhydrous organic solvent” means an organic solvent having a moisture content that is less than about 0.01% by weight of the total amount of water and organic solvent, unless otherwise defined herein.

The term “cannabinoid” includes Δ that includes trans-Δ ⁹ -THC and cis-Δ ⁹ -THC.
^9- THC; Δ ⁸ -THC, (−)-Δ ⁸ -iso-THC and (+)-Δ ⁸ -iso-THC
Structural isomers of Δ ⁹ -THC having the molecular formula C ₂₁ H ₃₀ O ₂ , including cannabinol and cannabinol structural isomers having the molecular formula of C ₂₁ H ₂₈ O ₂ ; Δ ⁹ -THC-carvone Acid; CBD, abn-CBD, (+)-abn-CBD, olivetol, (+)-
p-menta-2,8-dien-1-ol and (−)-p-menta-2,8-diene—
Δ ⁹ -THC precursors, including 1-ol; salts thereof; and acids, ethers,
These derivatives include esters, amines and the like.

Unless otherwise specified herein, the phrase “cannabinoid impurity” means a cannabinoid other than trans-(−)-Δ ⁹ -THC or trans-(+)-Δ ⁹ -THC.

Unless otherwise specified herein, the generic name “Δ ⁹ -THC-carboxylic acid” is
(−)-Δ ⁹ -THC-carboxylic acid, (+)-Δ ⁹ -THC-carboxylic acid, or (±)-
Means THC-carboxylic acid.

As used herein, the phrase “crystalline (±) -Δ ⁹ -THC” includes approximately equimolar amounts of trans-(−)-Δ ⁹ -THC and trans-(+)-Δ ⁹ -THC. An amount of trans-(−)-Δ ⁹ -TH that is at least about 95% by weight, based on the total amount of cannabinoids
It means Δ ⁹ -THC in solid form with C and trans-(+)-Δ ⁹ -THC.
As used herein, the term “patient” refers to animals of (but not limited to) cattle, horses, sheep, pigs, chickens, turkeys, quails, cats, dogs, mice, rats, rabbits, guinea pigs, and the like. Means animals such as mammals, more preferably mammals,
Most preferred is a human.
4.2. Purification method of trans-(−)-Δ ⁹ -THC

As noted above, the present invention provides at least about 98% by weight based on the total amount of cannabinoids.
Of trans-(−)-Δ ⁹ -THC or trans-(+)-Δ ⁹ -THC.

In one embodiment, the present invention provides a composition comprising (±) -Δ ⁹ -THC and an eluting solvent separated on a chiral stationary phase to produce trans-(−)-Δ ⁹ -THC or trans-(+)-
For a method comprising providing a Δ ⁹ -THC composition, the (±) -Δ ⁹ -THC is obtained from crystalline (±) -Δ ⁹ -THC. Without being limited by theory, Applicants believe that trans-(−)-Δ ⁹ -THC and trans-(+)-Δ ⁹ -THC are crystalline (±) -Δ ^9.
-THC, cannabinoid impurities commonly present in Δ ⁹ -THC compositions are:
I think it will be substantially, if not completely removed. Then, crystallinity (±) −Δ ⁹ −T
The (±) -Δ ⁹ -THC obtained from HC was resolved in the chiral stationary phase with the eluting solvent to give at least about 98 wt% trans-(−) − based on the total amount of cannabinoids.
A composition comprising Δ ⁹ -THC or trans-(+)-Δ ⁹ -THC is obtained.

In one embodiment, the present invention comprises separating a composition comprising (±) -Δ ⁹ -THC and an eluting solvent on a chiral stationary phase to provide a trans-(−)-Δ ⁹ -THC composition. , trans - (-) - relates to a process for the preparation of a composition comprising a delta ⁹ -THC, wherein the (±) - [delta ⁹ -
THC is obtained from crystalline (±) -Δ ⁹ -THC.

In other embodiments, the present invention provides that a composition comprising (±) -Δ ⁹ -THC and an eluting solvent is separated on a chiral stationary phase, resulting in a trans-(+)-Δ ⁹ -THC composition. including, trans - (+) - relates to a process for the preparation of a composition comprising a delta ⁹ -THC, wherein the (±) - [delta ⁹
-THC is obtained from crystalline (±) -Δ ⁹ -THC.

Crystalline (±) -Δ ⁹ -THC useful in the present invention can be obtained by any known or later developed method. For example, non-limiting method for obtaining crystalline (±) -Δ ⁹ -THC, as described below in Section 4.3, crystalline (±) -Δ ⁹ -
Trans-(−)-Δ ⁹ -THC, trans-(+)-Δ ⁹ -T for producing THC
Crystallization from a first composition comprising HC and a non-polar organic solvent may be mentioned.

In another embodiment, the present invention provides a composition comprising (±) -Δ ⁹ -THC and an eluting solvent separated on a chiral stationary phase to produce trans-(−)-Δ ⁹ -THC and trans-(+) −Δ ⁹
At least about 98% by weight of trans-(−)-Δ ⁹ -THC, based on the total amount of THC
Trans-(−) comprising providing a trans-(−)-Δ ⁹ -THC composition comprising
-(DELTA) ^9- THC is related with the preparation method of-(DELTA) ^9- THC composition, said (+)-(DELTA) ^9- THC is trans-(-).
Trans-(−)-Δ ⁹ -THC and trans-(+)-Δ ⁹ -THC from the first composition comprising -Δ ⁹ -THC, trans-(+)-Δ ⁹ -THC and a nonpolar organic solvent. Crystallized to give crystalline (±) -Δ ⁹ -THC and a liquid phase.

In another embodiment, the present invention provides a composition comprising (±) -Δ ⁹ -THC and an eluting solvent separated on a chiral stationary phase to produce trans-(+)-Δ ⁹ -THC and trans-(-). −Δ ⁹
At least about 98% by weight of trans-(+)-Δ ⁹ -THC, based on the total amount of THC
Trans-(+) comprising providing a trans-(+)-Δ ⁹ -THC composition comprising
-(DELTA) ^9- THC is related with the preparation method of-(DELTA) ^9- THC composition, said (+)-(DELTA) ^9- THC is trans-(-).
Trans-(−)-Δ ⁹ -THC and trans-(+)-Δ ⁹ -THC from the first composition comprising -Δ ⁹ -THC, trans-(+)-Δ ⁹ -THC and a nonpolar organic solvent. Crystallized to give crystalline (±) -Δ ⁹ -THC and a liquid phase.

Compositions comprising trans-(−)-Δ ⁹ -THC and trans-(+)-Δ ⁹ -THC useful for obtaining crystalline (±) -Δ ⁹ -THC are described in Section 4.3. It can be obtained by the method.
4.3. Crystallization stage

As noted above, crystalline (±) -Δ ⁹ -THC is, in one embodiment, trans-(-
) -Δ ⁹ -THC, trans-(+)-Δ ⁹ -THC and trans-(+)-Δ ⁹ -THC and trans-(+)-Δ ⁹ -THC were crystallized from a composition containing trans-(+)-Δ ⁹ -THC and a nonpolar organic solvent. Let me out (
"Crystallization stage"), can be obtained by producing crystalline (±) -Δ ⁹ -THC and a liquid phase. Useful for this crystallization stage is trans-(−)-Δ ⁹ -THC, trans-(+
The composition comprising)-[Delta] ^9- THC and a non-polar organic solvent can be obtained by any known or later developed method.

For example, crystalline (±) -Δ ⁹ -THC is obtained by contacting appropriate amounts of trans-(−)-Δ ⁹ -THC and trans-(+)-Δ ⁹ -THC with a nonpolar organic solvent. be able to. The order and rate of addition of trans-(−)-Δ ⁹ -THC, trans-(+)-Δ ⁹ -THC and non-polar organic solvent are not critical and may be performed sequentially or substantially simultaneously. In some cases. As an example, trans-(−)-Δ ⁹ -THC (optionally in the presence of a nonpolar organic solvent) and trans-(+)-Δ ⁹ -THC (optionally in the presence of a nonpolar organic solvent) Can be added to the nonpolar organic solvent. Similarly, trans-(+)-Δ ⁹ -THC in the presence of a nonpolar organic solvent and trans-(−)-Δ ⁹ -THC in the presence of a nonpolar organic solvent can be mixed.

Trans-(−)-Δ ⁹ -THC can be obtained from natural products or can be obtained by synthetic methods. In one embodiment, trans-(−)-Δ ⁹ -THC is obtained from natural products such as hashish or marijuana (Y. Gaoni et al., J. Am. Ch).
em. Soc. 93: 217 (1971); and Elsohly et al. US Pat. No. 6,365,416 B
1).

Trans-(−)-Δ ⁹ -THC is an acid catalyst such as p-toluenesulfonic acid, and cis / (+)-p-menta-2,8-dien-1-ol in the presence of a dehydrating agent. Reaction of trans mixture with olivetol (see Petrizilka, US Pat. No. 3,560,528 and Razdan et al., US Pat. No. 4,025,516); (−)-CBD in an inert solvent under anhydrous conditions Reaction with Lewis acids such as BF ₃ .Et ₂ O (see Razdan et al. US Pat. No. 4,025,516; and WO 03/070506); or (−)-Δ ⁸ -THC and HCl Reaction followed by dehydrochlorination (Y. Mechoulam
et al., J. Am. Chem. Soc. 89: 4553 (1967); and R. Mechoulam et al., J. Am. Chem
Soc. 94: 6159 (1972)), but also by known synthetic methods (but not limited to). Alternatively, trans-(−)-Δ ⁹ -THC can be obtained by the method described in Section 5.

Trans-(+)-Δ ⁹ -THC, which is not known to occur in nature, is (+)-Δ ^8.
-Reaction of THC with HCl followed by dehydrochlorination (R. Mechoulam et al., J. Am. Chem. So
c. 94: 6159 (1972)), but (but not limited to) known synthetic methods. Alternatively, trans-(+)-Δ ⁹ -THC can be obtained by the method described in Section 5. In one embodiment, the trans-(+)-Δ ⁹ -THC used in the crystallization stage is prior to (±) -Δ ⁹ -THC on the chiral stationary phase, as described in Section 4.4. “Recirculated” from the split.

In another embodiment, trans-(−)-Δ ⁹ -THC used in the crystallization stage
And trans-(+)-Δ ⁹ -THC can be obtained as a mixture of enantiomers by direct synthesis. When using synthetic methods, the ratio of trans-(−)-Δ ⁹ -THC to trans-(+)-Δ ⁹ -THC can vary depending on the optical purity of the reagents and the synthesis process. In one embodiment, trans-(−)-Δ ⁹ -THC and trans-
(+)-Δ ⁹ -THC is obtained in approximately equimolar amounts by a synthetic route using a racemic reagent. Trans-(−)-Δ ⁹ -THC and trans-(+)-Δ ^9- by the direct synthetic route
Non-limiting methods for preparing THC include the reaction of citral and olivetol in the presence of a Lewis acid (see R. Mechoulam et al., J. Am. Chem. Soc. 94: 6159 (1972)). Or (±) -1-m-nitrobenzenesulfonate with NaOH in aqueous methanol solution
Hydrolysis of 6a, 10a-trans-Δ ⁹ -THC (KE Fahrenholtz et al., J. Am.
Chem. Soc. 89: 5934-5941 (1967)). Or (±) -Δ ⁹ -THC
Can be obtained by the method described in Section 5.

In yet another embodiment, trans-(−)-Δ ⁹ − used in the crystallization stage.
THC and trans-(+)-Δ ⁹ -THC can be obtained from derivatives of trans-(−)-Δ ⁹ -THC and trans-(+)-Δ ⁹ -THC. For example, trans- (
-)-Δ ⁹ -THC and a mixture of trans-(+)-Δ ⁹ -THC are reacted with a phenol protecting group, such as m-nitrobenzenesulfonate, and crystallized to give 2-m-nitrobenzenesulfonate- (±)- Δ ⁹ -THC can be generated (Fahrenholt
z, U.S. Pat. No. 3,507,885; and KE Fahrenholtz et al., J. Am. Chem.
Soc. 89: 5934-5491 (1967)). Subsequently, the 2-m-nitrobenzenesulfonate- (±) -Δ ⁹ -THC was deprotected, and trans-(−)-Δ ⁹ -THC and trans- (
+)-Δ ⁹ -THC is crystallized from the composition comprising trans-(−)-Δ ⁹ -THC, trans-(+)-Δ ⁹ -THC and a nonpolar organic solvent. Let crystallinity (
±) -Δ ⁹ -THC can be generated.

Trans-(−)-Δ ⁹ -THC and trans-(+)-Δ ⁹ used in the crystallization stage
The ratio of -THC can vary. In one embodiment, trans-(−)-Δ ⁹ -T
HC is from about 0.75 to about 1.25 per mole equivalent of trans-(+)-Δ ⁹ -THC.
Present in a molar equivalent amount. In another embodiment, trans-(−)-Δ ⁹ -THC is
It is present in an amount of about 0.9 to about 1.1 molar equivalents per molar equivalent of trans-(+)-Δ ⁹ -THC. In other embodiments, trans-(−)-Δ ⁹ -THC is trans- (
+)-Δ ⁹ -THC is present in an amount of about 0.95 to about 1.05 molar equivalents per molar equivalent. And in other embodiments, trans-(−)-Δ ⁹ -THC is trans-(+
) -Δ ⁹ -THC is present in an amount of about 1 molar equivalent per molar equivalent.

Non-limiting examples of non-polar organic solvents that are useful in the crystallization stage include aliphatic (C) linear aliphatic hydrocarbons, branched aliphatic hydrocarbons and cycloaliphatic hydrocarbons or mixtures thereof. _{4 to} C ₁₀ ) hydrocarbons such as butane, pentane, hexane, heptane, octane,
Nonane and decane are listed.

In one embodiment, the nonpolar organic solvent used in the crystallization stage is a linear or branched heptane. In other embodiments, the nonpolar organic solvent used in the crystallization stage is pentane, hexane, heptane, octane or isooctane. In other embodiments, the nonpolar organic solvent used in the crystallization stage is n-heptane.

The amount of nonpolar organic solvent used in the crystallization stage can vary and will depend in part on the amount and type of cannabinoid impurities and the temperature. Generally, the nonpolar organic solvent is about 1% to about 9% by weight based on the total amount of Δ ⁹ -THC and the nonpolar organic solvent.
It is present in an amount sufficient to produce a mixture having a [Delta] ^9- THC concentration of 5 wt%, preferably from about 20 wt% to about 75 wt%, more preferably from about 40 wt% to about 60 wt%.

The crystallization stage is carried out for a time and at a temperature sufficient to produce (±) -Δ ⁹ -THC crystals. The time sufficient to crystallize (±) -Δ ⁹ -THC is from about 1 hour to about 200.
In other embodiments, from about 5 hours to about 150 hours; in other embodiments, from about 25 hours to about 100 hours; and in other embodiments, from about 30 hours to about 75 hours. It is.

In general, the temperature sufficient to produce crystalline (±) -Δ ⁹ -THC is about −78 ° C. to about 100 ° C .; in other embodiments, about −50 ° C. to about 25 ° C .; other embodiments From about −30 ° C. to about 0 ° C .; and in other embodiments from about −25 ° C. to about −15 ° C.

In certain embodiments, the crystallization stage is performed at two or more temperatures. In one embodiment, a composition comprising trans-(−)-Δ ⁹ -THC, trans-(+)-Δ ⁹ -THC and a nonpolar organic solvent is prepared at a first temperature, eg, 20 ° C. or higher. The Without being limited by theory, Applicants have determined that trans-(−)-Δ ⁹ -THC and trans- (to non-polar organic solvents by forming the composition at a temperature of 20 ° C. or higher.
+)-Δ ⁹ -THC is considered to have increased solubility. Thereafter, the temperature of the mixture can be lowered to a second temperature, eg, 0 ° C. or lower. Without being limited by theory, Applicants have determined that (±) −Δ ⁹ −TH by keeping the mixture at a temperature of 0 ° C. or lower.
It is considered that the solubility of C decreases and crystallization is promoted. Optionally, the temperature of the mixture may be further reduced to a third temperature, for example from -20 to -15 ° C. As noted above, such a decrease in temperature is believed to enhance the (±) -Δ ⁹ -THC crystallization process.

In one embodiment, trans - (-) - Δ ⁹ -THC and trans - (+) - Δ ⁹ -
THC is dissolved in a nonpolar organic solvent, the resulting solution is cooled to about 0 ° C., the resulting mixture is further cooled to about −15 ° C., and the resulting crystalline (±) -Δ ⁹ -THC is purified. Separate from the liquid phase.

In other embodiments, the crystallization step is performed in the presence of seed crystals. In general, the seed crystal is
When used, trans-(−)-Δ ⁹ -THC, trans-(+)-Δ ⁹ -THC
And a nonpolar organic solvent is added to the cooled (eg 0 ° C. or lower) mixture. In one embodiment, the seed crystal is (±) -Δ ⁹ -THC.

The progress of the crystallization stage can be monitored visually or by thin layer chromatography (
“TLC”), high performance liquid chromatography (“HPLC”), gas chromatography (“GC”), gas liquid chromatography (“GLC”), infrared spectroscopy (“IR”)
, Raman spectroscopy (“Raman”) and nuclear magnetic resonance spectroscopy (“NMR”), eg ¹ H
Alternatively, it can be monitored using conventional analytical techniques including but not limited to ¹ C NMR.

The crystallization stage can be carried out at reduced pressure, atmospheric pressure or high pressure. In one embodiment, the crystallization stage is performed at atmospheric pressure.

In one embodiment, prior to performing the crystallization step, trans-(−)-Δ ⁹ -THC and / or
Alternatively, certain impurities are removed from the trans-(+)-Δ ⁹ -THC composition. Non-limiting methods for removing impurities before performing the crystallization step include column chromatography (
(See section 4.4) or extraction under basic conditions as described below.

In one embodiment, (+)-Δ ⁹ -THC, (-)-Δ ⁹ -THC or (±) -Δ ⁹
-THC is contacted with a base before performing the crystallization step.

In another embodiment, the present invention provides trans-(+)-Δ ⁹ -THC, trans-(-
) -Δ ⁹ -THC or (±) -Δ ⁹ -THC purification method (“Δ ⁹ -THC purification method”), which comprises trans-(+)-Δ ⁹ -THC, trans- ( -)-Δ ⁹ -THC or trans- (±) -Δ ⁹ -THC is contacted with a first water-immiscible organic solvent, a water-miscible alcohol, water and an alkali metal hydroxide (“caustic alkali contact”). Stage (Caustic Cont
acting Step) "), (i) an alcohol-caustic phase comprising (i) a first organic phase and (ii) trans-(-)-Δ ⁹ -THC and trans-(+)-Δ ⁹ -THC
forming a two-phase mixture.

Without being limited by theory, trans-(−)-Δ ⁹ -THC, trans-(+)-
Impurities that may prevent or prevent crystallization of (±) -Δ ⁹ -THC from a composition comprising Δ ⁹ -THC and a non-polar organic solvent are caused by this caustic contact step to become Δ ⁹ -TH
It is considered that the C-containing alcohol-caustic phase is extracted into the first organic phase.

The amount of alkali metal hydroxide used in the caustic contact stage is generally Δ ⁹
Range from about 1 to about 1000 molar equivalents per mole equivalent of -THC; in other embodiments, the amount of alkali metal hydroxide is from about 10 to about 100 molar equivalents per mole equivalent of trans-Δ ⁹ -THC And in other embodiments, the amount of alkali metal hydroxide ranges from about 25 to about 55 molar equivalents per molar equivalent of trans-Δ ⁹ -THC.

Non-limiting examples of water-miscible alcohols useful in the caustic contact stage include methanol, ethanol, isopropanol, or any combination thereof. In one embodiment, the water miscible alcohol is methanol.

The amount of water miscible alcohol used in the caustic contact step is from about 1 part to about 100 parts by weight based on the weight of the alkali metal hydroxide; in other embodiments, the amount of water miscible alcohol The amount is from about 1 to about 25 parts by weight based on the weight of the alkali metal hydroxide; and in other embodiments, the amount of water-miscible alcohol is based on the weight of the alkali metal hydroxide. About 5 to about 10 parts by weight.

Non-limiting examples of first water immiscible organic solvents useful in the caustic contact stage include the nonpolar organic solvents described above for the crystallization stage. In one embodiment, the first water immiscible organic solvent is heptane.

The amount of the first water immiscible organic solvent used in the caustic contact step is generally Δ
^From about 1 to about 1000 parts by weight based on the weight of ^9- THC; in other embodiments, the amount of water-immiscible organic solvent is about 5 weights based on the weight of Δ ⁹ -THC. Parts to about 100 parts by weight; and in other embodiments, the amount of water-immiscible organic solvent is Δ ⁹ −
About 5 to about 20 parts by weight based on the weight of THC.

The caustic contact step can be performed by methods known in the art, such as, but not limited to, stirring, shaking, countercurrent cascades and ultrasound, mixing, pumping. The caustic contact step can also be performed by methods useful for liquid-liquid extraction (eg, Lo et al., Extraction, in 7 Kirk-Othmer Encyc. Of Chem. Techno
l. See 349-381 (4th ed. 1993). The entire contents of which are incorporated herein by reference)
.

The caustic contact stage is generally from about 0.25 hours to about 50 hours; in other embodiments, from about 0.25 hours to about 10 hours; and in other embodiments, from about 0.25 hours to about 2 hours. Done.

The caustic contacting step is generally performed at a temperature from about 0 ° C. to about 100 ° C .; in other embodiments, from about 20 ° C. to about 50 ° C .; and in other embodiments, from about 20 ° C. to about 30 ° C.

The caustic contact step can be performed at reduced pressure, atmospheric pressure (ie, about 1 atmosphere) or high pressure. In one embodiment, the caustic contact step is performed at atmospheric pressure.

The progress of the caustic contact stage can be monitored using conventional techniques as described above for the crystallization stage.

In other embodiments, the trans-Δ ⁹ -THC purification method of the present invention further comprises contacting the alcohol-caustic phase with an acid to produce an acid-treated alcohol phase. Without being limited by theory, trans-Δ ⁹ -THC is believed to be immiscible with the acidified alcohol phase. Non-limiting examples of useful acids include citric acid, acetic acid and the like. In one embodiment, the acid is citric acid.

Generally, the acid is added in an amount sufficient to achieve a pH of about 5 to about 9. In other embodiments, the acid is added in an amount sufficient to achieve a pH of about 6 to about 8; in other embodiments, the acid is used to achieve a pH of about 7 to about 8. Is added in a sufficient amount.

In other embodiments, the Δ ⁹ -THC purification method of the present invention comprises contacting the acid-treated alcohol phase with a second water-immiscible organic solvent to yield (i) trans-(−)-Δ ⁹ -THC. It further includes forming a second organic phase comprising and (ii) an acid treated alcohol phase.

Non-limiting examples of second water-immiscible organic solvents useful for contacting the acid-treated alcohol phase to form a second organic phase comprising trans-Δ ⁹ -THC include crystallization steps. And nonpolar organic solvents described above. In one embodiment, the second water immiscible organic solvent is heptane. The amount of the first water immiscible organic solvent used is generally trans-Δ ⁹
From about 1 to about 1000 parts by weight based on the weight of -THC; in other embodiments, the amount of water-immiscible organic solvent is about 1 based on the weight of trans-Δ ⁹ -THC. From about 50 parts by weight; and in other embodiments, the amount of water-immiscible organic solvent is:
About 1 to about 10 parts by weight based on the weight of Trans-Δ ⁹ -THC. Useful methods for contacting the acid-treated alcohol phase with a second water-immiscible organic solvent include those described above for the crystallization step.

In another embodiment, the Δ ⁹ -THC purification method of the present invention further comprises separating a second organic phase from the acid-treated alcohol phase. Useful methods for separating the second organic phase from the acid-treated alcohol phase include those described above for separating the first organic phase from the alcohol-caustic phase. After separation from the acid-treated alcohol phase, the second organic phase is generally separated, for example, by azeotropic distillation and / or with the second organic phase and a desiccant (eg Na ₂ SO ₄
Or dried by contact with MgSO ₄ ).

In other embodiments, the Δ ⁹ -THC purification method of the present invention further comprises concentrating the second organic phase to form a concentrated second organic phase comprising trans-Δ ⁹ -THC. A useful non-limiting method for concentrating the second organic phase is distillation. When the second organic phase is concentrated by distillation, this distillation can be carried out at high pressure, atmospheric pressure or reduced pressure. In one embodiment, the distillation is performed at atmospheric pressure. In other embodiments, the distillation is performed at reduced pressure.

In another embodiment, the Δ ⁹ -THC purification method of the present invention comprises contacting the concentrated second organic phase with a nonpolar organic solvent to form a first organic composition comprising trans-Δ ⁹ -THC. Further included. The amount and type of nonpolar organic solvent is that described for the nonpolar organic solvent in the crystallization stage above.

In other embodiments, trans-Δ ⁹ -THC used in the Δ ⁹ -THC purification method.
Includes trans-(−)-Δ ⁹ -THC. In other embodiments, the trans-Δ ⁹ -THC used in the Δ ⁹ -THC purification method comprises trans-(−)-Δ ⁹ -THC and trans-(+)-Δ ⁹ -THC. In other embodiments, the trans-Δ ⁹ -THC used in the Δ ⁹ -THC purification method comprises trans-(−)-Δ ⁹ -THC and trans-(+)-Δ ⁹ -THC, where Of trans-(−)-Δ ⁹ -THC is present in an amount of about 0.75 to about 1.25 molar equivalents per molar equivalent of trans-(+)-Δ ⁹ -THC.

In another embodiment, the Δ ⁹ -THC purification method of the invention comprises:
Trans-(−)-Δ ⁹ -THC or trans-(+)-Δ ⁹ -THC is replaced with (−)-Δ ⁹
Adding to the first organic composition in an amount sufficient to produce a second organic composition comprising -THC and trans-(+)-Δ ⁹ -THC (in this case, said trans-(-)- Δ ⁹
-THC is about 0.75 to about 1.2 per mole equivalent of trans-(+)-Δ ⁹ -THC.
Present in an amount of 5 molar equivalents); and as described above for the crystallization step, trans-(−)-Δ ⁹ -THC and trans-(+)-Δ ⁹ -THC are converted into their first organic Crystallized from the composition, crystallinity (±) −Δ ⁹ −T
It further includes producing HC.

In other embodiments, the Δ ⁹ -THC purification method of the present invention can be prepared by trans-(−)-Δ ⁹ -THC and trans-(+)-Δ ⁹ − as described above for the crystallization step. Crystallizing THC from the first organic composition to yield crystalline (±) -Δ ⁹ -THC, wherein (a) the first organic composition comprises (−)-Δ ⁹ -THC; And trans-(+)-Δ ⁹ -T
HC, and (b) the trans-(−)-Δ ⁹ -THC is trans-(+)
Present in the first organic composition in an amount of from about 0.75 to about 1.25 molar equivalents per molar equivalent of -Δ ⁹ -THC.

In another embodiment, the present invention provides trans-(−)-Δ ⁹ -THC, trans-(+
From) - [delta ⁹ first composition comprising -THC and a non-polar organic solvents, trans - (-) - Δ ⁹ -
THC and trans-(+)-Δ ⁹ -THC were crystallized to produce crystalline (±) -Δ ⁹ -THC.
Comprising causing relates to a manufacturing method of a crystalline (±) -Δ ⁹ -THC, wherein the trans - (-) - Δ ⁹ -THC and trans - (+) - Δ ⁹ -THC can,
(A) (i) a first organic phase comprising a first water-immiscible organic solvent, and (ii) trans-(-)
Forming a two-phase composition comprising an alcohol-caustic phase containing -Δ ⁹ -THC and trans-(+)-Δ ⁹ -THC;
(B) separating trans-(−)-Δ ⁹ -THC and trans-(+)-Δ ⁹ -THC from the alcohol-caustic phase; and (c) (i) the trans- of step (b) (−)-Δ ⁹ -THC and trans-(+)-
Obtained by forming a first composition comprising Δ ⁹ -THC and (ii) a nonpolar organic solvent.

A method of forming the two-phase composition, as well as a first water-immiscible organic solvent, a water-miscible alcohol,
The amount and type of water and alkali metal hydroxide include those described above for the caustic contact step. Similarly, trans from alcohol-caustic phase
(−)-Δ ⁹ -THC and trans-(+)-Δ ⁹ -THC separation method, and (i)
Trans-(−)-Δ ⁹ -THC and trans-(+)-Δ ⁹ -THC of step (b);
(Ii) A method for forming a first composition containing a nonpolar organic solvent includes (±) -Δ ⁹ -THC.
Those described above for the purification method may be mentioned.

Once obtained, the crystalline (±) -Δ ⁹ -THC formed in the crystallization stage can be separated from the liquid phase by methods known in the art. From liquid phase to crystallinity (±) -Δ
Examples of the method for separating ^9- THC include filtration, centrifugation, and decantation. In one embodiment, crystalline (±) -Δ ⁹ -THC is separated from the liquid phase by filtration.

The crystalline (±) -Δ ⁹ -THC formed in the crystallization stage can optionally be washed with an organic washing solvent and separated from the liquid phase as explained above. Crystalline (±) -Δ ⁹ -
When washing THC, the temperature of the organic wash solvent can vary. In general, cleaning
When performed, from about −78 ° C. to about 50 ° C .; in other embodiments, from about −30 ° C. to about 30
And in other embodiments, with an organic wash solvent at a temperature from about -20 ° C to about 25 ° C.

Examples of useful organic cleaning solvents include non-polar organic solvents as described above.
In one embodiment, the organic cleaning solvent, if used, is n-heptane.

The separated (±) -Δ ⁹ -THC may be dried in some cases. This drying can be performed at atmospheric pressure, optionally using a sweep gas such as dry air, nitrogen, helium or argon. Alternatively, (±) -Δ ⁹ -THC can be dried under reduced pressure.

When the separated (±) -Δ ⁹ -THC is dried, the drying temperature can vary. Generally, drying occurs at a temperature of about −25 ° C. to about 65 ° C .; in other embodiments, from about 0 ° C. to about 60 ° C .; and in other embodiments, from about 25 ° C. to about 50 ° C. be able to.

Generally, the (±) -Δ ⁹ -THC obtained in the crystallization stage is at least about 95% by weight of trans-(−)-Δ ⁹ -THC and trans-based on the total amount of cannabinoids.
(+)-Δ ⁹ -THC is included. In other embodiments, obtained at the crystallization stage (±)
-Δ ⁹ -THC comprises at least about 98% by weight of trans-(-)-Δ ⁹ -THC and trans-(+)-Δ ⁹ -THC, based on the total amount of cannabinoids. In other embodiments, the (±) -Δ ⁹ -THC obtained in the crystallization stage is at least about 99% by weight of trans-(−)-Δ ⁹ -THC and trans- (based on the total amount of cannabinoids.
+)-Δ ⁹ -THC.

The separated (±) -Δ ⁹ -THC can then be resolved with a chiral stationary phase as described in section 4.4 below.
4.4. Division stage

In the present invention, (±) -Δ ⁹ -THC obtained from crystalline (±) -Δ ⁹ -THC and the elution solvent are brought into contact with a chiral stationary phase to obtain a trans-(−)-enantiomer and trans-(+
) -Resolving enantiomers ("Resolving Step"). This provides at least about 98% by weight of trans-(−)-Δ ⁹ -TH based on the total amount of cannabinoids.
A composition comprising C or trans-(+)-Δ ⁹ -THC is obtained. Trans Without being limited by theory, the Applicant, by dividing the crystalline (±) - [delta ⁹ obtained from -THC (±) -Δ ⁹ -THC, obtained according to known methods - ( -) - delta ⁹ -THC or trans - (+) - cannabinoid impurities found in delta ⁹ -THC, has only low levels any, trans - (-) - delta ⁹ -THC or trans -
It is believed that a (+)-Δ ⁹ -THC composition is obtained.

The composition containing (±) -Δ ⁹ -THC used in this resolution step is trans- (
+) -Δ ⁹ -THC less than, equal to or greater than trans- (
-)-Δ ⁹ -THC can be contained. For example, a composition comprising (±) -Δ ⁹ -THC may be converted to crystalline (±) -Δ ⁹ -THC by trans-(−)-Δ ⁹ -THC composition and / or trans- ( It can be obtained by mixing with (+)-Δ ⁹ -THC. In general, a composition comprising (±) -Δ ⁹ -THC is obtained in about equimolar amounts of trans-(-)-
Contains Δ ⁹ -THC and trans-(+)-Δ ⁹ -THC.

Any known or later developed chiral stationary phase that resolves trans-(−)-Δ ⁹ -THC and trans-(+)-Δ ⁹ -THC can be used. For example, a transformer
A method for resolution of (−)-Δ ⁹ -THC enantiomers and trans-(+)-Δ ⁹ -THC enantiomers with a chiral stationary phase is described by SL Levin et al., J. Chromatogr. A 654: 5.
3-64 (1993). In general, a chiral stationary phase contains a chiral group or derivative immobilized on a support such as a polymer or an inorganic oxide. A non-limiting example of a useful polymer support is polystyrene in the form of beads. Non-limiting examples of useful inorganic oxide supports include silica, magnesium silicate, magnesia, alumina, and molecular sieves. In one embodiment, the inorganic oxide support is silica.

Said chiral derivative comprises at least one chiral center. Non-limiting examples of useful chiral derivatives include, for example, amylose, cellulose, chitocin, xylan, kurdran,
Tris (aryl carbamate) derivatives of saccharides such as dextran and inulin. In one embodiment, the saccharide is amylose.

In one embodiment, the tris (arylcarbamate) is tris (3,5-dimethylphenylcarbamate), tris (4-chlorophenylcarbamate), tris (4
-Methyl carbamate), tris (4-methylbenzoate) or tris [(S) -phenylethyl carbamate]. In another embodiment, the tris (arylcarbamate) is tris (3,5-dimethylphenylcarbamate). In another embodiment, the chiral stationary phase is Daicel Chemi of Tokyo, Japan.
cal Industries) available as Chiralpak (R) AD (TM),
Amylose tris (3,5-dimethylphenyl carbonate) fixed on silica.

Other non-limiting examples of useful chiral stationary phases include: cellulose triacetate; cellulose tribenzoate; poly [(S) -N-acryloylphenylalanine ethyl ester]; 3,5-dinitrobenzoylphenylglycine; 3,5-dimethylbenzoyl) -L-diallyltartramide; bridged di- (4-tert-butylbenzoyl)-
L diallyltartramide; and tetrahydro-aminophenanthrene 3,5-dinitrobenzamide (ER Francotte, J. Chromatogr. A 906: 379-397 (2001).
reference).

In general, a concentrated solution of (±) -Δ ⁹ -THC and the elution solvent are added to the top (or front) of the column containing the chiral stationary phase. Thereafter, (±) -Δ ⁹ -THC was dissolved in the elution solvent (
That is, eluting with mobile phase) and trans-(−)-Δ ⁹ -THC or trans-(+
) Resulting in an eluate containing -Δ ⁹ -THC.

The resolution step can be performed by batch chromatography, continuous chromatography or simulated moving bed chromatography (eg ER Francotte, J. Chromatogr. A 906: 379-397 (2001)
Reference). In one embodiment, the resolution step is performed using continuous chromatography.

The resolution step can be performed at about 1 atmosphere, or optionally at reduced pressure or pressure.
In one embodiment, the splitting stage is performed at about 1 atmosphere. In other embodiments, the splitting stage is performed at high pressure. In one embodiment, the resolution step uses flash chromatography at moderate high pressure, such as about 1.1 to 10 atmospheres, about 1.1 to about 5 atmospheres, or about 1.1 to about 1.3 atmospheres. Done. In other embodiments, the resolution step is performed using flash chromatography at very high pressure, for example from about 10 to about 175 atmospheres, from about 100 to 175 atmospheres, from about 125 to about 175 atmospheres, or about 150 atmospheres.

Non-limiting examples of elution solvents useful in the resolution step include one or more —O
Linear or branched (C ₁ -C ₄ ) alkyl substituted with H, —OR ₁ , —OC (O) R ₁ , —C (O) OR ₁ , —halo or —CN; Branched chain (C ₄ -C ₁₀ ) aliphatic hydrocarbons; (C ₅ -C ₇ ) alicyclic hydrocarbons optionally substituted with one or more —R ₁ ; one or more (C ₄ -C ₇ ) cyclic ether optionally substituted with —R ₁ ; one or more of —R ₁ , —halo, —CH ₂ (halo), —CH (halo)
₂ , aromatic hydrocarbon optionally substituted with —C (halo) ₃ , —O (C ₁ -C ₆ ) alkyl; or any mixture thereof, wherein R ₁ is (C _{1 ~C 4)} alkyl.

Straight or branched chain (C ₁ -C) substituted with one or more —OH, —OR ₁ , —OC (O) R ₁ , —C (O) OR ₁ , —halo or —CN. ₄ ) Non-limiting examples of alkyl include methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, chloromethane, methylene chloride, chloroform, carbon tetrachloride chloride, diethyl ether, Di-isopropyl ether, tert-butyl methyl ether, acetonitrile, methyl formate, ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate, or any mixture thereof.

Non-limiting examples of straight chain or branched (C ₄ -C ₁₀ ) aliphatic hydrocarbons include butane, pentane, hexane, heptane, isooctane, nonane, decane, or any mixture thereof.

Non-limiting examples of (C ₅ -C ₇ ) alicyclic hydrocarbons optionally substituted with one or more —R ₁ include cyclopentane, cyclohexane, methylcyclohexane, cycloheptane, or these Any mixture of

Non-limiting examples of (C ₄ -C ₇ ) cyclic ethers optionally substituted with one or more —R ₁ include tetrahydrofuran, methyltetrahydrofuran, 1,4-dioxane, 1,3-dioxolane. Or any mixture thereof.

Optionally substituted with one or more —R ₁ , —halo, —CH ₂ (halo), —CH (halo) ₂ , —C (halo) ₃ , —O (C ₁ -C ₆ ) alkyl. Non-limiting examples of aromatic hydrocarbons that may be mentioned include toluene, xylene, chlorobenzene, benzotrifluoride, or any mixture thereof.

In one embodiment, the elution solvent includes an aliphatic hydrocarbon and an alcohol. In another embodiment, the elution solvent comprises n-heptane and isopropanol. In another embodiment, the organic solvent is n-heptane: 2-propanol (95: 5 (v
/ V)) including the mixture.

The progress of the splitting phase can be monitored using the analytical method described in section 4.3 above.

An eluate containing trans-(−)-Δ ⁹ -THC and substantially free of other cannabinoids can be combined. In one embodiment, the eluate is trans-(−)-Δ ⁹ −.
At least about 98% by weight, based on the total amount of THC and trans-(+)-Δ ⁹ -THC
Trans-(−)-Δ ⁹ -THC; in other embodiments, at least about 99 wt% trans-(−)-Δ ⁹ -THC; in other embodiments, at least about 99.5 wt%
Trans-(−)-Δ ⁹ -THC; and in other embodiments, at least about 99.
Contains 9% by weight of trans-(−)-Δ ⁹ -THC.

Similarly, an eluate containing trans-(+)-Δ ⁹ -THC and substantially free of other cannabinoids can be combined. In one embodiment, the eluate is trans-(+)
At least about 98, based on the total amount of -Δ ⁹ -THC and trans-(-)-Δ ⁹ -THC.
Wt% trans-(+)-Δ ⁹ -THC; in other embodiments, at least about 99 wt% trans-(+)-Δ ⁹ -THC; in other embodiments, at least about 99.5
Wt% trans-(+)-Δ ⁹ -THC; and in other embodiments at least about 99.9 wt% trans-(+)-Δ ⁹ -THC.

First solvent and trans-(−)-Δ ⁹ -THC or trans-(+)-Δ ⁹ -THC
The eluate containing may optionally be separated from the volatile components to give each enantiomer as an oil. Examples of the method for separating trans-(−)-Δ ⁹ -THC or trans-(+)-Δ ⁹ -THC from volatile components include distillation at atmospheric pressure or reduced pressure. For example, trans-(−)-Δ ⁹ -THC or trans-(+)-Δ ⁹ -THC, if desired, can be distilled by fractional distillation to yield trans-(−)-Δ ⁹ -THC or A trans-(+)-Δ ⁹ -THC fraction can be obtained (see, eg, Olsen et al. US Pat. No. 4,381,399).
4.5. A composition comprising trans-(−)-Δ ⁹ -THC or trans-(+)-Δ ⁹ -THC

As mentioned above, the present invention provides trans-(−)-Δ ⁹ -THC or trans-(+)
It also relates to a composition comprising -Δ ⁹ -THC.

In one embodiment, the present invention provides at least 99 based on the total amount of cannabinoids.
. 0% by weight trans-(−)-Δ ⁹ -THC; in other embodiments, at least about 9
9.5 wt% trans-(−)-Δ ⁹ -THC; and in other embodiments, relates to a composition comprising at least 99.9 wt% trans-(−)-Δ ⁹ -THC.

In one embodiment, the present invention provides at least 99 based on the total amount of cannabinoids.
. It relates to a composition comprising from 0% to about 99.95% by weight of trans-(−)-Δ ⁹ -THC. In another embodiment, the invention relates to a composition comprising at least 99.0% to about 99.98% by weight of trans-(−)-Δ ⁹ -THC, based on the total amount of cannabinoids.

In other embodiments, at least 99.0% by weight, based on the total amount of cannabinoids.
A composition comprising trans-(−)-Δ ⁹ -THC is formulated as a pharmaceutical composition as described in Section 4.6.

In one embodiment, the present invention provides at least 99 based on the total amount of cannabinoids.
. 0% by weight of trans-(+)-Δ ⁹ -THC; in other embodiments, at least about 9
9.0.0 wt% trans-(+)-Δ ⁹ -THC; in other embodiments, at least 99.5.0 wt% trans-(+)-Δ ⁹ -THC; and other embodiments A composition comprising at least 99.9% by weight of trans-(+)-Δ ⁹ -THC.

The trans-(−)-Δ ⁹ -THC composition of the present invention is trans-(−) — derived from natural sources.
Can be found in delta ⁹ -THC compositions delta ⁹ -THC carboxylic acid (RF Turk et
al., J. Pharm. Pharmac. 23: 190-195 (1971)) is generally not included. In one embodiment, the trans-(−)-Δ ⁹ -THC composition of the present invention comprises less than 0.05% Δ ⁹ -THC carboxylic acid, based on the total amount of cannabinoids; .
Delta ⁹ -THC carboxylic acid of less than 0.1%; in another embodiment, less than 0.005% Δ ⁹ -
THC carboxylic acids; and in other embodiments, contain less than 0.001% Δ ⁹ -THC carboxylic acid. In other embodiments, the trans-(−)-Δ ⁹ -THC composition comprises
Does not contain Δ ⁹ -THC carboxylic acid.

In other embodiments, the invention provides at least 9 based on the total amount of cannabinoids.
9.0 wt% trans-(−)-Δ ⁹ -THC and less than 0.05% Δ ⁹ -THC carboxylic acid; in other embodiments, at least about 99.5 wt% trans-(−) — Δ ⁹
-THC and less than 0.05% delta ⁹ -THC carboxylic acid; and in another embodiment, at least 99.9% by weight of trans - (-) - Δ ⁹ -THC and less than 0.05% delta ⁹ - It relates to a composition comprising THC carboxylic acid.

In other embodiments, the invention provides at least 9 based on the total amount of cannabinoids.
9.0 wt% trans-(+)-Δ ⁹ -THC and less than 0.05% Δ ⁹ -THC carboxylic acid; in other embodiments, at least about 99.5 wt% trans-(+) — Δ ⁹
-THC and less than 0.05% delta ⁹ -THC carboxylic acid; and in another embodiment, at least 99.9% by weight of trans - (+) - Δ ⁹ -THC and less than 0.05% delta ⁹ - It relates to a composition comprising THC carboxylic acid.

As described above, trans-(+)-Δ ⁹ -T together with trans-(−)-Δ ⁹ -THC
HC is useful for the production of crystalline (±) -Δ ⁹ -THC.

The trans-(−)-Δ ⁹ -THC or trans-(+)-Δ ⁹ -THC composition can be prepared by the methods described above.

In another embodiment, the present invention provides (-)-[Delta] ^9- THC, trans-(+)-[Delta] ^9- T.
It relates to a composition comprising HC, a first water-immiscible organic solvent, a water-miscible alcohol, water and an alkali metal hydroxide. This composition comprises (−)-Δ ⁹ -THC and / or trans- (
+) Useful for removing impurities from -Δ ⁹ -THC.
4.6. Therapeutic / prophylactic administration of a composition comprising trans-(−)-Δ ⁹ -THC

At least 99.0% by weight of trans-(−)-Δ based on the total amount of cannabinoids
The composition of the present invention containing ⁹ -THC is trans - (-) - same disease delta ⁹ -THC is known to be useful (Diseases), disease (Ailments) or disorder (disorders) ( "
Conditions ") or trans-(-)-Δ ⁹
-THC is useful in any condition that is later found to be useful for treatment or prevention. For example, a trans-(−)-Δ ⁹ -THC composition comprising at least 99.0% by weight of trans-(−)-Δ ⁹ -THC, based on the total amount of cannabinoids, may cause vomiting, weight loss, anorexia, It may be useful in the treatment or prevention of multiple sclerosis, Tourette syndrome, Parkinson's disease, or paralysis, such as cerebral palsy. Accordingly, in one embodiment, the present invention comprises administering an effective amount of a trans-(−)-Δ ⁹ composition to a patient in need thereof,
It also relates to a method for treating or preventing a condition, said trans-(-)-
The Δ ⁹ -THC composition is at least 99.0% by weight, based on the total amount of cannabinoids.
Of trans-(−)-Δ ⁹ -THC; in other embodiments, at least 99.0% by weight
Of trans-(−)-Δ ⁹ -THC; in another embodiment, at least 99.5% by weight
Trans-(−)-Δ ⁹ -THC; and in other embodiments, at least 99.9
Contains% by weight of trans-(−)-Δ ⁹ -THC.

In other embodiments, the invention also relates to a method for treating or preventing a condition comprising administering to a patient in need thereof an effective amount of a trans-(−)-Δ ⁹ composition, the trans - (-) - Δ ⁹ -THC composition, based on the total amount of cannabinoids, at least 99.0% by weight of trans - (-) - Δ less than ⁹ -THC and 0.05 wt% delta ⁹ -THC carboxylic acid; in another embodiment, at least 99.0 wt%
Trans-(−)-Δ ⁹ -THC and less than 0.05% by weight Δ ⁹ -THC carboxylic acid;
In other embodiments, at least 99.5% by weight of trans-(−)-Δ ⁹ -THC and less than 0.05% by weight of Δ ⁹ -THC carboxylic acid; and in other embodiments, at least 99.9% by weight. % Trans-(−)-Δ ⁹ -THC and less than 0.05% by weight Δ ⁹ -THC carboxylic acid.

  In one embodiment, the condition is pain.

In another embodiment, the condition is vomiting, eg, vomiting as a result of cancer chemotherapy.

  In another embodiment, the condition is anorexia.

In other embodiments, the condition is weight loss, eg, weight loss as a result of symptomatic HIV infection, including acquired immune deficiency syndrome (AIDS) or AIDS-related syndrome (ARC).

When administered to a patient, the trans-(−)-Δ ⁹ -THC composition containing at least about 99.0% by weight of trans-(−)-Δ ⁹ -THC, based on the total amount of cannabinoids, A suitable amount of a pharmaceutically acceptable carrier is included to produce a form for proper administration to the patient.

In certain embodiments, the term “pharmaceutically acceptable” is approved by a federal or state supervisory authority, or the United States Pharmacopeia or other for use in animals, and more particularly in humans. It means that it is described in a generally recognized pharmacopoeia. The term "carrier" is at least about 99.0% by weight of trans based on the total amount of cannabinoids - (-) - trans containing delta ⁹ -THC - (-) - used to administer the delta ⁹ -THC Refers to a diluent, adjuvant, excipient or vehicle. Such pharmaceutical carriers can be liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil and sesame oil. Pharmaceutical carriers can be saline, gum arabic, gelatin, starch paste, talc, keratin, colloidal silica, urea, and the like. In addition, auxiliaries, stabilizers, thickeners, lubricants and colorants may be used. The composition can also contain minor amounts of wetting or emulsifying agents, and / or pH buffering agents, if desired. When administered to a patient, these pharmaceutically acceptable carriers are preferably sterile.

The composition is in the form of a solution, suspension, emulsion, tablet, pill, pellet, capsule, liquid-containing capsule, powder, sustained release formulation, suppository, emulsion, aerosol, spray, suspension, or use Any other suitable form can be taken.

In one embodiment, at least about 99.0% by weight, based on the total amount of cannabinoids.
Trans - (-) - trans containing ^{Δ 9 -THC - (-) -} Δ 9 -THC composition,
Further includes sesame oil. In another embodiment, the trans-(− containing at least about 99.0 wt% trans-(−)-Δ ⁹ -THC based on the total amount of cannabinoids.
) -Δ ⁹ -THC composition further comprises sesame oil and the resulting mixture is encapsulated (see, eg, US Pat. No. 6,703,418 B2).

In other embodiments, the trans-(−)-Δ ⁹ -THC composition containing at least about 99.0% by weight of trans-(−)-Δ ⁹ -THC, based on the total amount of cannabinoids, as a tablet Molded.

At least about 99.0% by weight of trans-(-)-, based on the total amount of cannabinoids
Trans containing ^{Δ 9 -THC - (-) -} Δ 9 -THC composition, by any suitable flight route, for example by infusion or bolus injection, by absorption through epithelial or mucocutaneous reline (lining) (e.g., oral (Such as mucosa, rectal and intestinal mucosa) and can be administered together with another bioactive agent. Administration may be systemic,
It can be local. Encapsulation in a variety of delivery systems such as liposomes, microparticles, microcapsules, capsules, etc. is known and can be used to administer the pharmaceutical composition. As the administration method, intradermal administration, intramuscular administration, intraperitoneal administration, intravenous administration,
Subcutaneous, intranasal, epidural, oral, sublingual, intranasal, intracerebral, vaginal, transdermal, rectal, inhalation, or ear, nose, eye or Examples include, but are not limited to, topical administration to the skin. The preferred mode of administration is oral administration,
Other modes of administration may be left to human decision on site.

When used for oral delivery, at least about 99.0 based on the total amount of cannabinoids.
A trans-(−)-Δ ⁹ -THC composition containing% by weight of trans-(−)-Δ ⁹ -THC can be, for example, a tablet, lozenge, aqueous or oily suspension, granule, powder, emulsion,
It can be in the form of a capsule, syrup or elixir. An orally administered composition may be one or more of any drug, such as a sweetener (
For example, fructose, aspartame or saccharin); flavoring agents (eg, peppermint, wintergreen oil or cherry); colorants; and preservatives. Furthermore, when in tablet or pill form, the composition can be coated to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over an extended period of time. A selectively permeable membrane surrounding the osmotically active driving compound is also suitable for a pharmaceutical composition for oral administration. In these latter platforms, the driving compound absorbs liquid from the environment surrounding the capsule and swells to displace the drug or drug composition through the opening. These delivery platforms can produce an essentially zero-order delivery profile as opposed to the spiked profile of immediate release formulations. A time delay material such as glycerol monostearate or glycerol stearate may be used. Oral compositions can include standard carriers such as mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, and the like. Such carriers are preferably of pharmaceutical grade.

When used for intravenous delivery, at least about 99.99 based on the total amount of cannabinoids.
A trans-(−)-Δ ⁹ -THC composition containing 0% by weight of trans-(−)-Δ ⁹ -THC is formulated according to routine procedures for intravenous administration to humans. Preferably, the pharmaceutical composition for intravenous administration is a solution in a sterile isotonic aqueous buffer, optionally with a solubilizer. Intravenous compositions may optionally include a local anesthetic such as lignocaine to reduce pain at the site of the injection. Generally, these ingredients are supplied separately or mixed together in unit dosage form, for example, as a lyophilized dry powder or anhydrous concentrate in a hermetically sealed container such as an ampoule or sachet indicating the amount of active agent Is done. Where the pharmaceutical compositions are to be administered by infusion, they can be dispensed, for example, in an infusion bottle containing pharmaceutical grade sterile water or saline with optional solubilizers. When the pharmaceutical composition is administered by injection, an ampoule of sterile water for injection or physiological saline may be provided so that the ingredients can be mixed prior to administration.

Trans- containing at least about 99.0% by weight of trans-(−)-Δ ⁹ -THC, based on the total amount of cannabinoids, effective for the treatment or prevention of certain conditions
The amount of (−)-Δ ⁹ -THC composition can be determined by standard clinical methods. In addition, in vivo or in vitro assays can optionally be employed to help identify optimal dosages. The exact dose that can be used will also depend on the route of administration and the severity of the condition, and can be determined according to the judgment of the person in the field and / or the environment of each animal. Based on the total amount of cannabinoids, at least about 99.
When a trans-(−)-Δ ⁹ -THC composition containing 0 wt% trans-(−)-Δ ⁹ -THC is administered orally, its effective dosage is about every 4 hours, about 0.005mg
/ (Kg body weight) to about 0.4 mg / (kg body weight), but generally about 0.1 mg
/ (Kg body weight) or less. In one embodiment, the effective dosage is about 0.
. 005 mg / (kg body weight) to about 0.4 mg / (kg body weight); in another embodiment, the effective dosage is about 0.01 mg / (kg body weight) to about 0.1 mg / (kg body weight). In other embodiments, and the effective dosage is about 0.01 mg /
(Kg of body weight) to about 0.075 mg / (kg of body weight).

Oral dosage forms are generally about 0.1 mg to about 20 mg; in other embodiments, about 2.5 mg
In other embodiments, it comprises trans-(−)-Δ ⁹ -THC in an amount of about 10 mg; in other embodiments, about 2.5 mg; in other embodiments, about 5 mg;

In one embodiment, an effective dosage is administered about every 24 hours until the condition is ameliorated. In another embodiment, an effective dosage is administered about every 12 hours until the condition is ameliorated. In another embodiment, an effective dosage is administered about every 8 hours until the condition is ameliorated. In another embodiment,
Effective doses are administered approximately every 6 hours until the condition is ameliorated. In another embodiment, an effective dosage is administered about every 4 hours until the condition is ameliorated.

In certain embodiments, it may be desirable to introduce the pharmaceutical composition into the central nervous system by any suitable route, including intracerebroventricular injection and subarachnoid injection. Intraventricular injection can be facilitated by an intraventricular catheter, for example, attached to a reservoir, such as an Ommaya reservoir.

Transpulmonary administration can also be utilized, for example, by using an inhaler or nebulizer and a formulation with an aerosolizing agent, or by perfusion with a fluorocarbon or synthetic lung surfactant. In certain embodiments, the pharmaceutical composition can be formulated as a suppository, with traditional binders and carriers such as triglycerides.

In other embodiments, the trans-(−)-Δ ⁹ -THC composition containing at least about 99.0% by weight of trans-(−)-Δ ⁹ -THC, based on the total amount of cannabinoids, is a vesicle Can be delivered in particular liposomes (Langer, Science 249: 1527-1533 (199
0); Treat et al., In Liposomes in the Therapy of Infectious Disease and Cancer,
Lopez-Berestein and Fidler (eds.), Liss, New York, pp. 353-365 (1989); Lopez-
(See Berestein, ibid., Pp. 317-327; generally see the same book).

In other embodiments, the trans-(−)-Δ ⁹ -THC composition containing at least about 99.0% by weight of trans-(−)-Δ ⁹ -THC based on the total amount of cannabinoids is controlled release. Can be delivered by the system. In one embodiment, a pump can be used (Langer, supra; Sefton, CRC Crit. Ref. Biomed. Eng. 14: 201 (1987); Bu
chwald et al., Surgery 88: 507 (1980); Saudek et al., N. Engl. J. Med. 321: 574 (1
989)). In other embodiments, polymeric materials can be used (Medical A
pplications of Controlled Release, Langer and Wise (eds.), CRC Pres., Boca Raton
, Fla. (1974); Controlled Drug Bioavailability, Drug Product Design and Performa
nce, Smolen and Ball (eds.), Wiley, New York (1984); Ranger and Peppas, J. Macro
mol. Sci. Rev. Macromol. Chem. 23:61 (1983); Levy et al., Science 228: 190 (
1985); During et al., Ann. Neurol. 25: 351 (1989); Howard et al., J. Neurosurg. 7
See also 1: 105 (1989)). In other embodiments, the controlled release system can be placed in close proximity to the target of the pharmaceutical composition and therefore requires only a small amount of systemic dose (eg, Goodson, in Medical Applications of Controlled Release , supra, vol.
2, pp. 115-138 (1984)). Langer reviews the critic (Science 249: 1527-1533 (1990
Other controlled release systems discussed in)) may be used.

The present invention relates to one or more charged with a trans-(−)-Δ ⁹ -THC composition containing at least about 99.0% by weight of trans-(−)-Δ ⁹ -THC, based on the total amount of cannabinoids. A pharmaceutical pack or kit comprising more containers is also provided. A note in the form instructed by the government agency that oversees the manufacture, use or sale of a pharmaceutical or biological product,
In some cases, it may be associated with such containers, and this notice represents an approval by the institution for manufacture, use or sale for human administration.

The following examples are set forth to assist in understanding the invention and are not intended to limit the invention described and claimed herein. Such variations of the invention, including the substitution of all currently known or later developed equivalents and minor changes to the formulation or experimental design that would be within the skill of the art, are within the scope of the invention. Get inside.

5. EXAMPLES Unless otherwise stated, all reactions were performed under an argon or nitrogen atmosphere.

Unless otherwise stated, the phrases “cold water”, “cold hexane” or “cold heptane” mean water, hexane or heptane at a temperature from about 0 ° C. to about 5 ° C., respectively.

Reagents and solvents: Unless otherwise stated, all reagents and solvents are Aldrich.
Purchased from the Chemical Company and used without further purification.

High performance liquid chromatography: High performance liquid chromatography (HPLC) was performed under the following conditions, and the purity of the sample eluate was calculated from the resulting area percentage:

Standard HPLC is 3 μm C ₁₈ -stationary phase column (150 × 4.6 mm); mobile phase of the following composition: THF (71%), MeOH (24%) and water (5%) over 25 minutes,
THF (71%), MeOH (5%) and water (24%) over 10 minutes and 1
Gradient to THF (71%), MeOH (24%) and water (5%) over 0 minutes; 1
with a flow rate of mL / min; and a UV detector at 228 nm.

Chiral HPLC Method 1 consists of a 20 μm Chiralpak AD 250 × 4.6 mm column; a heptane: isopropanol (95: 5 (v: v)) mobile phase; a flow rate of 1 mL / min;
And using a UV detector at 228 nm. The sample concentration was approximately 1 mg per mL of heptane.

Chiral HPLC method 2 is 5 μm Chiralpak AD-H 250 × 4.6.
mm (Diacel) column; for CBD, hexane: ethanol (95: 5 (v:
v)) and Δ ⁹ -THC for hexane: isopropanol (90:10 (v: v
)) Mobile phase; flow rate of 1 mL / min; and UV detector at 228 nm. The sample concentration was approximately 1 mg per mL of hexane.

Gas chromatography: Gas chromatography (GC) is performed under the following conditions:
The purity of the eluate was calculated from the area percentage obtained:

Standard GC is HP-5 capillary column (length -30 m, ID -0.25 mm); 5% diphenyl / 95% dimethyl) polysiloxane (0.25 μm film) stationary phase; 230 ° C.
270 ° C. detector / temperature (FID); and hold at 100 ° C. for 3 minutes, rise to 240 ° C. at 10 ° C. per minute, hold at 240 ° C. for 10 minutes, rise to 270 ° C. per minute, and This was done using an oven temperature program using holding at 270 ° C. for 10 minutes. The concentration of the GC sample was about 1 mg per mL of EtOH.

Chiral GC uses Alpha-DEX-120, 30mx0.25mm column;
Standard G, except that the injection temperature was 250 ° C; the oven temperature was 90 ° C (constant temperature)
C was carried out in the same manner as described above.

X-ray powder diffraction diagram: X-ray powder diffraction analysis was performed using PANALYTICAL (Philips) X
'Pert Pro MPD powder X-ray diffraction system (CuKα ray, PW3050 / 60
This was carried out by a known method using a goniometer, PW3011 / 20 proportional detector). A Bragg-Brentano method was used for beam focusing.

Nuclear magnetic resonance spectroscopy: Nuclear magnetic resonance (NMR) spectra are (unless stated otherwise) C
Bruker AM-200 ( ¹ H at 200 MHz, 50 using DCl ₃ as solvent.
Recorded on a ¹³ C) or Bruker AM-400 ( ¹ H at 400 MHz) instrument. The chemical shift is δ (ppm) relative to internal TMS.

Melting point: Melting point determination can be performed in an open capillary using a Buchi B-545 capillary melting point measuring device, or with a Mettler-Toledo FP-81 melting point accessory and F
This was done using a P-900 processor. Melting points are uncorrected.

5.1. Synthesis of (−)-cis-p-ment-2,8-dien-1-ol Preparation of (−)-(1R, 2R, S5) -2-phenylthio-8-p-menten-1-ol: -)-Limonene oxide (152.2 g, 1.00 mol (about 1: 1 cis: trans diastereomeric mixture) (Aldrich Chemical), thiophenol (60.6 g, 0.55 mol) (Fluka Chemical, Buchs, Switzerland)
), Potassium carbonate (82.9 g, 0.60 mol), N, N-dimethylformamide (1
8.9 g, 0.26 mol) and toluene (400 mL) under Ar atmosphere
The mixture was stirred at 117 ° C. for 19 hours. The mixture was cooled to 25 ° C. and water (300 mL) was added. The resulting organic phase was collected and the aqueous layer was extracted with toluene (3 × 200 mL). The combined organic phases were washed with water (1 × 400 mL) and a 15% solution of brine (1 × 410 mL). The organic phase was then dried over Na ₂ SO ₄ (30 g) and filtered, and the resulting filtrate was subjected to pressure under pressure.
Concentrated at 65 ° C. The resulting brown oil (200.5 g) was fractionally distilled under reduced pressure to give 90.
(−)-Cis-limonene oxide (33.7 g) (1.1) with a purity (GC) of 2%
mbar 28.1 ° C. to 32.1 ° C.) and (−)-(1R, 2R, 4S) -2-phenylthio-8-p-menten-1-ol (147.4 g) (128 m at 1.2 mbar).
1 ° C. to 138.2 ° C.). (−)-(1R, 2R, 4S) -2-phenylthio-8
The analytical sample of -p-menten-1-ol had a melting point of 50-51 ° C (hexane) and a purity of 99.0% (GC).

Optical rotation: [α] _D ²⁰ -110 ° (c = 1.55, CHCl ₃ ).

¹ H NMR was consistent with the structure.

Preparation of (1R, 2R, 4S) -1-hydroxy-8-p-menthen-2-phenylsulfoxide: (−)-(1R, 2R, 4S) -2-phenylthio-8-p-menthen-1-
All (147 g; 0.56 mol) was dissolved in methyl alcohol (1.35 L) with stirring in an Ar atmosphere at 25 ° C., and the resulting solution was cooled from −10 ° C. to −5 ° C. To the methyl alcohol solution was added OXONE® (potassium peroxymonosulfate) (279.1 g, 0.448 mol) (Aldrich Chemical) in water (1.35 L).
al) was added dropwise at -10 ° C to -5 ° C over 2 hours and the resulting mixture was stirred at -10 ° C to -5 ° C for an additional 30 minutes. The mixture was warmed to 20 ° C. to 25 ° C., water (2.1 L) was added and the resulting biphasic mixture was dichloromethane (3 × 910 mL).
Extracted with. The combined organic phases were dried over sodium sulfate and filtered, and the resulting filtrate was concentrated under reduced pressure at 60 ° C. to give 150.9 g of residue. The residue is then chromatographed on a silica gel column (eluent: n-heptane / ethyl acetate 9: 1, then 8
: Purified by 2). (1R, 2R, 4S) -1-hydroxy-8-p-menthen-
Fractions mainly containing 2-phenylsulfoxide were combined and concentrated under vacuum for 10 hours at 40-50 ° C. to give (1R, 2R, 4S) -1-hydroxy-8-p-menthen-2-
Phenyl sulfoxide was obtained as a mixture of two diastereomers. Yield: 86.1 g
55.2%. This product was stored in a freezer.

(−)-Cis-p-menta-2,8-dien-1-ol: dimethyl sulfoxide (9
(1R, 2R, 4S) -1-hydroxy-8-p-menthen-2-phenylsulfoxide (86 g, 0.31 mol) and piperidine (71.0 g, 0.83 mol) in 10 mL).
) Was heated to 163 ° C. under Ar flow atmosphere, and the resulting mixture was stirred at 163 ° C. for 3 hours. The mixture was cooled to 20-25 ° C., treated with water (800 mL) and extracted with diethyl ether (2 × 400 mL). The combined organic phases were washed with 1N HCl (160 mL),
Washed with 7% sodium bicarbonate solution (150 mL), brine (150 mL) and dried over sodium sulfate. The organic phase was then concentrated under reduced pressure. The obtained residue (93.
3g) was purified by silica gel column chromatography (eluent: n-heptane, then n-heptane: ethyl acetate (1: 9 (v: v)) and (-)-cis-p-mentor-
Fractions mainly containing 2,8-dien-1-ol were combined and 40 ° C to 50 ° C under reduced pressure.
For 10 hours to give (−)-cis-p-menta-2,8-dien-1-ol. Yield: 26.1 g; 55%. Analysis of the product (GC) showed that it was 90.
It was 9%.

Optical rotation: [α] _D ²⁵ -69 ° (neat).

¹ H NMR was consistent with the structure.

5.2. Synthesis of (+)-cis-p-ment-2,8-dien-1-ol (+)-p-menta-2,8-dien-1-ol was synthesized from (+)-limonene oxide (1
: 1 cis / trans diastereomer mixture) was prepared as described in Example 1 except that (-)-limonene oxide was used instead. Analysis of the product obtained (G
C) showed it to have a purity of 91.0%.

Optical rotation: [α] _D ²⁵ + 78 ° (neat).

5.3. Synthesis of (±) -cis-p-ment-2,8-dien-1-ol (±) -p-menta-2,8-dien-1-ol is equivalent to (−) of Example 2 -P-
It was prepared by mixing menta-2,8-dien-1-ol and (+)-p-menta-2,8-dien-1-ol of Example 1.

5.4. Synthesis of (+)-CBD Synthesis of crude (+)-CBD (3b): olivetol (3.6 g, 20 mmol), zinc chloride (3.5 g, 26 mmol), water (3.5 mL, 19 mmol) and dichloromethane (35 mL) ) Was refluxed for 1 hour. To the refluxing mixture was added dichloromethane (1
(-)-P-menta-2,8-dien-1-ol (3.0 g, 20 mmol) in 0 mL).
l) was added dropwise over 0.75 hours and the resulting reaction mixture was mixed at reflux for 0.5 hours. The mixture was cooled to 25 ° C., ice water (50 mL) was added and the resulting biphasic mixture was stirred for 20 minutes at 0 ° C. The resulting organic phase was collected and washed with water (2 × 20 mL) and 5% NaHCO ₃ (20 mL). The organic phase was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give 6.0 g of first crude (+)-CBD residue. This first crude (
+)-CBD residue analysis (GC) shows that (+)-CBD (46.9%) and ab
It was shown to contain n-(−)-CBD (19.7%). The first crude (+)-CB
The D residue was purified by column chromatography on silica gel (eluent MTBE / hexane) to give 2.4 g of the second crude (+)-CBD residue.

Synthesis of (+)-CBD-bis (3,5-dinitrobenzoate) (4b): 3,5-dinitrobenzoyl chloride (3.4 g, 14.7 mmol) in dichloromethane (10 mL)
Of 0 ° C. to 5 ° C. second crude (+)-CBD residue (2.4 g), 4, N, N-dimethylaminopyridine (0.05 g), pyridine (6 mL) and dichloromethane (15
mL) was added dropwise to the stirred mixture. The mixture was allowed to warm to 25 ° C. for 2 hours.
Stir at 25 ° C. The mixture was then poured into a mixture of 37% HCl (6 mL), ice (75 g) and dichloromethane (50 mL). The resulting organic phase was collected, washed with brine (15 mL), 5% NaHCO ₃ (15 mL), dried over Na ₂ SO ₄ and filtered. The resulting filtrate was concentrated under reduced pressure to give 5.2 g of crude (+)-CBD-bis (3,5
-Dinitrobenzoate) (4b) was obtained. 10: 1 isopropanol and ethyl acetate (
A solution of the crude (+)-CBD-bis (3,5-dinitrobenzoate) (5.2 g) in a vol: vol mixture (70 mL) was stirred overnight at 25 ° C. and filtered. The resulting precipitate was dissolved in a 10: 1 (vol: vol) mixture of isopropanol and ethyl acetate (3 ×
10 mL) and dried under reduced pressure to give crystalline (+)-CBD-bis (3,5-dinitrobenzoate) (4b). Yield: 3.7 g, 26.5%.

  Melting point: 90-92 ° C. (decomposition (dec.)).

Optical rotation: [α] _D ²⁰ + 80 ° (c = 0.4, CHCl ₃ ).

Synthesis of (+)-CBD (3b): crystalline (+)-CBD-bis (3,5-dinitrobenzoate) (4b) (3.5 g, 5.0 mmol), butylamine (3.7 g, 50 mm)
ol) and toluene (20 mL) were stirred at room temperature for 12 hours and concentrated under reduced pressure. The residue obtained is chromatographed on silica gel (eluent hexane: MT).
Purification by BE (70: 1 (v: v)) gave 1.3 g of (+)-CBD as an oil. A solution of (+)-CBD (1.3 g) in hexane (1 mL) was kept at −15 ° C. overnight. The resulting mixture is then filtered and the resulting solid is dried under reduced pressure to give (+
) -CBD (3b) was obtained as white crystals. Yield: 1.2 g, 64%. Analysis of the product (GC) showed it to be 98.6% pure.

  Melting point: 64-66 ° C

Optical rotation: [α] _D ²⁰ + 126 ° (c = 0.12, 95% EtOH).

5.5. Preparation of (±) -Δ ⁸ -THC A solution of methanesulfonic acid (1.1 g, 11 mmol) in dichloromethane (6 mL) was added to olivetol (10.0 g, 55.5 mmol) and (±) in dichloromethane (130 mL). -P-Menta-2,8-dien-1-ol (8.5 g, 55.5 mmol)
To the solution. The resulting mixture was refluxed for 4 hours while removing water using a Dean-Stark separator. The mixture was then cooled to 25 ° C. and treated with aqueous NaHCO ₃ solution. The resulting organic phase was collected and concentrated under reduced pressure. The resulting residue was dissolved in heptane (110 mL), washed with 10% NaOH (130 mL), and the resulting organic phase was concentrated under reduced pressure to give 15.6 g of crude (±) -Δ ⁸ -THC. Got. Analysis of the crude product (GC) showed it to have a purity of 61.7%.

5.6. (-) - Preparation of crude ^{Δ 8 -THC (-) - Δ} 8 -THC (2a) is, (+) - p-mentha-2,8-dien-1-ol (±)-p-Mentha - The crude (±) -Δ ⁸ -THC was prepared as described in Example 5 except that it was used in place of 2,8-dien-1-ol.

5.7. (+) - Preparation of crude ^{Δ 8 -THC (+) - Δ} 8 -THC (2b) is, (-) - p-mentha-2,8-dien-1-ol (±)-p-Mentha - The crude (±) -Δ ⁸ -THC was prepared as described in Example 5 except that it was used in place of 2,8-dien-1-ol.

5.8. Two-part synthesis of trans-(−)-Δ ⁹ -THC Synthesis of (−)-CBD (3a): (+)-p-menta-2,8-dien-1-ol (844) in dichloromethane (325 mL) 0.5 g, 0.56 mol) was added to 40 ° C. olivetol (100.0 g, 0.56 mol), zinc chloride (100.3 g, 0.72 mo).
l) To a stirred mixture of water (10.0 mL, 0.56 mol) and dichloromethane (1 L) was added dropwise over 1 hour. The mixture was stirred for an additional 30 minutes at 40 ° C.
The mixture was cooled to 25 ° C., poured into ice water (500 g), and the resulting biphasic mixture was stirred at 0 ° C. for 20 minutes. The resulting organic phase was collected and washed with cold water (2 × 250 mL). The organic phase was collected and concentrated under reduced pressure to give a first residue (185.5 g). Analysis of the first residue (GC) showed that it was (−)-CBD (51.8%), abn-CBD (13.2%
), Olivetol (8.0%) and dialkylated olivetol (13.4%).

The first residue (185.5 g) was dissolved in n-heptane (1.1 L) and the resulting solution was mixed with 10% sodium hydroxide solution (1.3 L). The organic phase obtained is recovered and water (
250 mL) and concentrated under reduced pressure to give an oily brown second residue (124.3 g). Analysis of the second residue (GC) showed that it was (−)-CBD (66.0%), abn−
CBD (0.0%), olivetol (0.0%) and dialkylated olivetol (16
. 8%).

The second residue (124.3 g) was fractionally distilled (171 ° C. to 178 ° C .; 0.1 mmHg)
As a result, a fraction of 87.0 g was obtained. Analysis of the fraction (GC) shows that it is 74.3% (-)
-It was shown to contain CBD.

The fraction (87.0 g) was dissolved in 57 ° C. heptane (425 mL) and filtered. The resulting filtrate was cooled to 0 ° C. to 5 ° C. and ˜0.02 mg of powdery crystalline (−)-CBD (3a
) As seed crystals. The solution containing the seed crystals was stirred at 0 ° C. to 5 ° C. for 5 hours, and then stirred at −15 ° C. to −20 ° C. for 48 hours. The resulting mixture was filtered and the resulting solid was washed with cold heptane. The solids were then dried at 40 ° C. under reduced pressure, and (−)
-CBD (3a) was obtained. Yield: 39.2 g; 22%. Analysis of the product (GC) showed that it was (−)-CBD (3a) (97.1%) and trans-(−)-Δ ⁹ -THC (1
a) (1.44%). The structure of 3a was confirmed by ¹ H NMR spectroscopy. An analytical sample was prepared by recrystallizing a portion of crude 3a from heptane as described above.

  Melting point: 64-65 ° C.

Optical rotation: [α] _D ²⁰ -132 ° (c = 0.12, 95% EtOH).

Synthesis of trans-(−)-Δ ⁹ -THC (1a): A solution of 15.0 g (47.8 mmol) of crystalline (−)-CBD (3a) in anhydrous dichloromethane (45 mL) was added under an Ar atmosphere, − BF ₃ .Et ₂ O (8.4 g, 59 in anhydrous dichloromethane (180 mL) at 10 ° C.
. 2 mmol) was added dropwise over 1 hour. The mixture for 2 hours,
The mixture was stirred at 10 ° C. and poured into ice water (100 g). The resulting biphasic mixture was further stirred at 0 ° C. for 20 minutes. The resulting organic phase was collected and washed with cold water (50 mL), 7% aqueous sodium bicarbonate (50 mL) and water (50 mL). The organic phase was dried over Na ₂ SO ₄ and filtered. The obtained filtrate was concentrated at 40 ° C. under reduced pressure to obtain trans-(−)-Δ ⁹ -THC (
1a) was obtained as a yellow oil. Yield: 14.9 g, 99%. Analysis of the product (GC) showed that it contained 81.9% trans-(−)-Δ ⁹ -THC (1a).

One-pot synthesis of trans-(−)-Δ ⁹ -THC Olivetol (50.0 g, 0.28 mol), zinc chloride (50.0 g, 0.36 mo)
l) and anhydrous dichloromethane (510 mL) were stirred at 40 ° C. for 1 h under Ar atmosphere. (+)-P-Menta-2,8-dien-1-ol (42.2 g, 0.28
mol) and dichloromethane (155 mL) were added dropwise to the stirred olivetol containing mixture over 1 hour and the resulting mixture was stirred for an additional 40 minutes at 40 ° C. The mixture was cooled to −10 ° C. and BF ₃ Et ₂ O in anhydrous dichloromethane (37 mL).
A solution of (23.6 g, 166 mmol) was added dropwise over 1 hour. The resulting mixture was stirred at −10 ° C. for 1.5 hours. Cold water (250 mL) was added and the resulting organic phase was collected, cold water (120 mL), 7% aqueous sodium bicarbonate (120 mL) and water (1
20 mL). The organic phase was dried over Na ₂ SO ₄ (30 g) and filtered. The resulting filtrate was concentrated under reduced pressure to give trans-(−)-Δ ⁹ -THC (1a) as a brown oil. Yield: 89.14 g, 4 based on the trans-(−)-Δ ⁹ -THC content in the oil
6%. Analysis of the product (GC) showed that it was trans-(−)-Δ ⁹ -THC (1a) (
45.1%), (−)-Δ ⁸ -THC (5.06%) (2a), (−)-Δ ⁸ -iso-TH
C (17.6%), CBD (3a) (0.71%), olivetol (7.95%) and dialkylated olivetol (10.8% by weight), trans-(+)
-Δ ⁹ -THC (1b) was not detected.

A solution of trans-(−)-Δ ⁹ -THC oil (20.0 g) in heptane (120 mL) was carefully washed with 10% NaOH (150 mL) and water (50 mL), dried over Na ₂ SO ₄ , Filtered. The resulting filtrate was then concentrated under reduced pressure to give a first crude residue (1
6.6 g) which was 38.5% by weight of trans-(-) using HPLC.
Containing -Δ ⁹ -THC (1a) and using GC, trans-(−)-Δ ⁹
-THC (1a) (47.4%), [Delta] ^8- THC (2a) (8.6%), [Delta] ⁸ -iso-TH
It contained C (19.6%), CBD (0.5%), olivetol (0.0%) and dialkylated olivetol (10.9%).

A solution of the first crude residue (16.5 g) in heptane (240 mL) was extracted with an aliquot of 9% NaOH in 80% methanol (3 × 180 mL). The combined basic methanol extracts were acidified with 20% citric acid to about pH 7 and extracted with heptane (3 × 90 mL). The combined organic fractions were washed with water (50 mL), dried over Na ₂ SO ₄ and filtered. The resulting filtrate was then concentrated under reduced pressure to give 13.7 g of crude residue, which was
When C was used, 44.0% by weight of trans-(−)-Δ ⁹ -THC was contained, and when GC was used, trans-(−)-Δ ⁹ -THC (1a) (51.8 %), Δ ⁸ −
THC (2a) (10.0%), Δ ⁸ -iso-THC (22.3%), CBD (0.0%
), Olivetol (0.0%) and dialkylated olivetol (1.3%).

5.10. Synthesis of trans-(+)-Δ ⁹ -THC A solution of BF ₃ .Et ₂ O (0.34 g, 2.4 mmol) in anhydrous dichloromethane (8 mL) was run in anhydrous dichloromethane (50 mL) at −5 ° C. Crystalline (+)-C from Example 4
To a solution of BD (3a) (1.1 g, 3.6 mmol) was added dropwise over 1 hour with stirring. The resulting mixture was stirred at −5 ° C. for 1.5 hours. The mixture is iced (100
g) and 7% NaHCO ₃ (100 mL). The organic phase obtained is recovered,
The aqueous phase was extracted with dichloromethane (2 × 20 mL). The combined organic phases were washed with water (20 mL), dried over Na ₂ SO ₄ and filtered. The obtained filtrate was concentrated at 40 ° C. under reduced pressure.
The resulting residue was purified by column chromatography on silica gel (stationary phase) using MTBE: hexane (1: 100 to 3: 100 (v: v)) as the eluent.
Crude trans-(+)-Δ ⁹ -THC (1b) was obtained as a yellow oil: yield: 0.7 g.
Analysis of the crude trans-(+)-Δ ⁹ -THC (GC) showed it to be 92.6% pure.

5.11. One-pot synthesis of trans-(+)-Δ ⁹ -THC Olivetol (14.21 g, 79.6 mmol), zinc chloride (14.25 g, 102
. 6 mmol) and anhydrous dichloromethane (145 mL) were stirred at 40 ° C. for 1 h. (−)-P-Menta-2,8-dien-1-ol (12.00 g, 76.6 m
ol) and anhydrous dichloromethane (45 mL) are added dropwise to the stirred olivetol containing mixture at 40 ° C. over 1 hour and the resulting mixture is added for an additional 40 minutes at 40 ° C.
And stirred. The mixture was cooled to −10 ° C. and BF in anhydrous dichloromethane (12 mL).
A solution of ₃ · Et ₂ O (6.7 g, 47 mmol) was added dropwise over 1 hour at −10 ° C. The mixture was stirred at −10 ° C. for 30 minutes. Cold water (50 mL) was added and the resulting biphasic mixture was stirred at 0 ° C. for an additional 20 minutes. The resulting organic phase was collected and cold water (2 × 5
0 mL), washed with 5% aqueous sodium bicarbonate (50 mL) and water (50 mL).
Thereafter, the organic phase was concentrated under reduced pressure at 40 ° C., and the resulting residue (24.8 g) was added at 25 ° C.
-Dissolved in heptane (140 mL). The resulting solution was added to a 10% aqueous KOH solution (124 mL
), Water (2 × 50 mL), dried over MgSO ₄ (10 g) and filtered. The obtained filtrate was concentrated at 40 ° C. under reduced pressure. Thereafter, the obtained residue (20.7 g) was reduced in pressure (0
. Fractional distillation under 1 mbar) to give trans-(+)-Δ ⁹ -THC (1b). Yield: 17.16 g, 69%. Analysis of the product (GC) shows that it is trans-(+)-Δ
^9- THC (1b) (49.2%), Δ ⁸ -iso-THC (25.31%) and dialkylated olivetol (1.29%) are shown to contain trans-(−)-Δ ⁹ -TH
C (1a) was not detected.

5.12. Synthesis of (±) -Δ ⁹ -THC A solution of BF ₃ .Et ₂ O (0.3 g, 2.1 mmol) in anhydrous dichloromethane (8 mL) was added to (±) in anhydrous dichloromethane (45 mL) at −5 ° C. -CBD (1.0 g, 3.2
mmol) was added dropwise over 1 hour with stirring. The resulting mixture is 1
. Stir for 5 hours at -5 ° C. The mixture was then added to 7% NaHCO ₃ (50 mL). The resulting organic phase was collected and the aqueous phase was extracted with dichloromethane (3 × 30 mL). The combined organic phases were washed with brine (20 mL), dried over Na ₂ SO ₄ and filtered. The resulting filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography using silica gel (stationary phase) and MTBE: hexane (1: 100 to 2: 100 (v: v)) as eluent to give crude (±) -Δ ^9- THC was obtained as a yellow oil.
Yield: 0.6 g, 56%. The analysis (GC) of the (±) -Δ ⁹ -THC oil shows that it is 92.
It was shown to have a purity of 6%. The oily (±) -Δ ⁹ -THC (0.6 g) was dissolved in hexane (0.5 mL) and the resulting mixture was maintained at −15 ° C. for 24 hours. The resulting mixture was filtered, washed with cold hexane (3 × 1 mL), dried under reduced pressure and (±) −Δ ⁹
-THC was obtained as slightly rose crystals. Yield: 0.4g. Melting point: 65-66 ° C.

5.13. One-pot synthesis of (±) -Δ ⁹ -THC Olivetol (11.84 g, 65.7 mmol), zinc chloride (11.87 g, 85.
4 mmol) and anhydrous dichloromethane (120 mL) were stirred at 40 ° C. for 1 h. (+)-P-Menta-2,8-dien-1-ol (5.00 g, 32.84 mol)
), (−)-P-menta-2,8-dien-1-ol (5.00 g, 3
2.84 mol) and anhydrous dichloromethane (37 mL) were added dropwise to the stirred olivetol containing mixture over 1 hour at 40 ° C. and the resulting mixture was further added 4
Stir for 0 min at 40 ° C. The mixture was cooled to −10 ° C. and anhydrous dichloromethane (10
A solution of BF ₃ .Et ₂ O (5.6 g, 39.4 mmol) in mL) was added dropwise over 1 hour at −10 ° C. The mixture was stirred for 30 minutes at −10 ° C. and 50 mL of cold water was added. The resulting biphasic mixture was stirred at 0 ° C. for an additional 20 minutes. The resulting organic phase was collected and cooled water (2 × 50 mL), 8% aqueous sodium bicarbonate (50 mL) and water (50
mL). The organic phase was concentrated at 40 ° C. under reduced pressure. Residue obtained (20.5 g)
Was dissolved in n-heptane (115 mL) at 25 ° C., washed with 10% aqueous KOH solution (100 mL) for 40 minutes at 25 ° C., and washed with water (50 mL). Thereafter, the organic phase is reduced under reduced pressure to 50
Concentration at 0 ° C. gave 17.1 g of crude (±) -Δ ⁹ -THC as a brown oil.

A portion of the crude (±) -Δ ⁹ -THC oil (2.4 g) was dissolved in a minimum amount of heptane and one cylinder (50 mm × 210 mm LUNA CM 10 μm; load capacity 60
Merck-Knauer PP K-1800 at 0 mg; eluent: n-heptane)
Purified by single pass chromatography using preparative chromatograph. (
Fractions containing ±) -Δ ⁹ -THC were combined and concentrated under reduced pressure at 40 ° C. to give (±) -Δ ⁹ -T.
HC (1) was obtained. Yield: 1.1 g. Analysis of the product (GC) shows that it is (±) -Δ ⁹
-THC (1) (91.27%), iso-Δ ⁸ -THC (1.87%) and Δ ⁸ -THC
(1.08%).

Preparation of (±) -Δ ⁹ -THC Olivetole (15.0 g, 83.2 mmol), zinc chloride (15.0 g, 108 mm
ol) and anhydrous dichloromethane (150 mL) were stirred at 40 ° C. for 1 h.
A solution of (±) -p-menta-2,8-dien-1-ol (12.7 g, 83.2 mmol) and anhydrous dichloromethane (45 mL) was added to the stirred olivetol-containing mixture.
One drop was added over 1 hour at 0 ° C. and the resulting mixture was added for an additional 0.50 hours at 40 ° C.
And stirred. The mixture was cooled to −10 ° C. and BF in anhydrous dichloromethane (11 mL).
A solution of ₃ • Et ₂ O (7.1 g, 49.4 mmol) was added dropwise to the mixture at −10 ° C. over 1 hour. The mixture was stirred for 0.50 hours at −10 ° C. and 80 mL
Of cold water was added with stirring to form a biphasic mixture. The organic phase is recovered and cold water (80 m
L) Washed with 5% aqueous sodium bicarbonate (80 mL) and water (80 mL). The organic phase was dried over Na ₂ SO ₄ , filtered, and the resulting filtrate was concentrated under reduced pressure to give 28.5 g of first crude (±) -Δ ⁹ -THC residue. Analysis of the residue it, was used HPLC, (±) where - [delta ⁹ containing -THC (30.3%), and was used ^{GC, (±) -Δ 9 -THC} ( 45.2%), Δ ⁸ -THC (3.2%), (±) -Δ ⁸ -iso-THC (17.3%), CBD (4.0%), olivetol (8.3%) and It was shown to contain dialkylated olivetol (11.7%).

A portion (28.5 g) of the first crude (±) -Δ ⁹ -THC residue was heptane (165 m
L) and the resulting solution was washed with 10% NaOH (200 mL) and water (80 mL). The organic solution was then dried by azeotropic distillation and concentrated under reduced pressure to give a second crude (±) -Δ ⁹ -THC residue. Yield: 23.5 g, 37.6%. The second crude (±
) -Δ ⁹ -THC residue was analyzed using (±) -Δ ⁹ -TH using HPLC.
Containing C (37.6%) and using GC, (±) -Δ ⁹ -THC (50
. 7%), Δ ⁸ -THC (3.8%), (±) -Δ ⁸ -iso-THC (19.6%), CB
D (4.4%), olivetol (0.0%) and dialkylated olivetol (12.8)
%).

5.15. Preparation of (±) -Δ ⁹ -THC from a mixture of crude raw materials of trans-(−)-Δ ⁹ -THC and trans-(+)-Δ ⁹ -THC Trans-(−)-Δ ⁹ -THC is (+)-P-menta-2,8-dien-1-ol was used instead of (±) -p-menta-2,8-dien-1-ol,
The crude second (±) -Δ ⁹ -THC residue was prepared as described in Example 14. Analysis (HPLC) of the resulting crude trans-(−)-Δ ⁹ -THC showed that it contained 41.4 wt% trans-(−)-Δ ⁹ -THC.

Trans-(+)-Δ ⁹ -THC replaces (−)-p-menta-2,8-dien-1-ol with (±) -p-menta-2,8-dien-1-ol. Except that I used it
The crude second (±) -Δ ⁹ -THC residue was prepared as described in Example 14. Analysis (HPLC) of the resulting crude trans-(+)-Δ ⁹ -THC showed it to contain 37.5 wt% trans-(−)-Δ ⁹ -THC.

The crude trans-(−)-Δ ⁹ -THC (24.3 g; 10.0 g of trans-(−
) -Δ ⁹ -THC) and trans-(+)-Δ ⁹ -THC (26.7 g; 10.0 g of trans-(+)-Δ ⁹ -THC) were dissolved in heptane (425 mL) at 25 ° C. The resulting solution was mixed with 2 × 180 mL of 9% aqueous NaOH: methanol (20:80 (v: v)) solution. Combine the methanol phases and adjust the pH from 0 ° C. to about 5 ° C. until the pH is about 7.
Treated with 0% citric acid. Heptane (290 mL) was added and the resulting organic phase was washed with water. The organic phase was then dried over Na ₂ SO ₄ , filtered and the resulting filtrate was concentrated under reduced pressure to give 41.8 g of crude (±) -Δ ⁹ -THC as a brown oil. Crude (±) -Δ ⁹
Analysis of -THC (HPLC) showed it to be 48% pure.

The crude (±) -Δ ⁹ -THC (41.8 g) was dissolved in heptane (85 mL), the resulting solution was cooled to 0 ° C., and crystalline (±) -Δ ⁹ -THC (100 mg) was seeded. Put as crystals. The resulting mixture was further cooled to −15 ° C. for 12 hours and filtered. The resulting solid was washed with cold heptane (3 × 10 mL) and dried under reduced pressure to give (±) -Δ ⁹ -THC as a white crystalline solid. Yield: 8.7 g, 43%. Analysis (HPLC) of the product is
It was shown to have a purity of 96.5%. Its crystallinity (±) -Δ ⁹ -THC is 2
After at least 3 days at 5 ° C., it remained white.

5.16. Preparation of (±) -Δ ⁹ -THC from (±) -Δ ⁸ -THC Preparation of (±) -9-chloro-trans-hexahydrocannabinol: Crude (±) -Δ ^8- from Example 5 A mixture of THC (15.6 g; 9.63 g (±) -Δ ⁸ -THC), zinc chloride (4.66 g, 34.23 mmol) and anhydrous dichloromethane (310 mL) was added for 0.5 h at 25 ° C. under Ar atmosphere. Stir below. The mixture was cooled to 0 ° C. and the mixture was bubbled with gaseous hydrogen chloride for 1.5 hours. The mixture was poured into an ice bath (150 g) and the resulting biphasic mixture was stirred for 1 hour at 0-5 ° C. The organic phase was collected and cold water (2x
100 mL), 8% sodium bicarbonate solution (100 mL) and water (100 mL). The organic phase was dried over anhydrous Na ₂ SO ₄ (15 g) and filtered. Thereafter, the obtained filtrate was concentrated at 30 ° C. under reduced pressure. The obtained residue (16.3 g) was dissolved in n-heptane (33
(mL), cooled to 0 ° C., and (±) -9-chloro-trans-hexahydrocannabinol (0.01 g) was added as a seed crystal. The resulting mixture was then stirred at 0 ° C. for 5 hours, cooled to −15 ° C. and stirred at −15 ° C. for 60 hours. The mixture was filtered and the resulting solid was washed with cold n-heptane (14 mL). Thereafter, the solid was reduced to 50 ° C. under reduced pressure.
To give (±) -9-chloro-trans-hexahydrocannabinol. Yield: 5.7 g; 32.7%. Analysis (HPLC) of the (±) -9-chloro-trans-hexahydrocannabinol showed it to be 95.2% pure. The analytical sample recrystallized from heptane had a melting point of 89-90 ° C. The purity (HPLC) of the analytical sample was 99.6%.

Optical rotation: [α] _D ²⁰ 0.0 ° (c = 0.53, CHCl ₃ ).

¹ H NMR was consistent with the structure.

¹³ C NMR (CDCl ₃ ) δ 13.9, 19.1, 22.4, 24.2, 27.6,
30.4, 31.3, 31.5, 34.1, 35.3, 42.0, 44.8, 48.7,
72.6, 76.7, 107.7, 108.9, 110.0, 142.8, 154.5,
155.0.

The powder X-ray diffraction pattern of the crystalline (±) -9β-Cl—HHC is about 7.5, 11.2, 1
3.3, 14.9, 15.4, 15.9, 19.4, 19.7, 20.0 and 22.5
And a characteristic peak represented by a diffraction angle 2θ.

Preparation of (±) -Δ ⁹ -THC: Potassium-tert-amylate (6.6 g), (±)
-9-chloro-trans-hexahydrocannabinol (5.7 g, 16.2 mmol)
And a mixture of anhydrous toluene (280 mL) was stirred at 65 ° C. for 75 minutes. The mixture was cooled to 25 ° C. and poured into ice water (100 g). The resulting organic phase was collected and cooled with cold water (2 ×
100 mL), 7% sodium bicarbonate, and water (2 × 100 mL). The organic phase was then dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The resulting residue (5.35 g
) In n-heptane (3.4 mL), cooled to 0 ° C. and (±) -Δ ⁹ -THC (0.
01 g) was added as seed crystals. The resulting mixture was stirred at 0 ° C. for 5 hours, cooled to −15 ° C., and stirred at −15 ° C. for 60 hours. The mixture was filtered and the resulting solid was washed with cold n-heptane (4 ml). Thereafter, the solids were dried at 50 ° C. under reduced pressure, and (±) −
Δ ⁹ -THC was obtained. Yield: 3.3 g, 64.7%. Analysis (HPLC) of the product is
It was shown to have a purity of 97.23%.

5.17. (±) -Δ ⁹ -THC Purification of (±) -Δ ⁹ -THC m- nitrobenzenesulfonate: A mixture of the second crude (±) -Δ ⁹ -THC residue of Example 14 (20.0 g; 7.52 g (±) -Δ ⁹ -THC), chloride 3
-Nitrobenzenesulfonyl (14.5 g, 65.4 mmol), triethylamine (9
. 7 g) and dichloromethane (300 mL) were stirred at 25 ° C. for 1 h. The resulting mixture was then treated with cold water (200 mL). The resulting organic phase is recovered and 1
Washed sequentially with 0% HCl (80 mL), water (100 mL), 5% NaHCO ₃ (100 mL) and water (100 mL). The organic phase was then dried over Na ₂ SO ₄ and filtered.
The resulting filtrate was concentrated under reduced pressure to give 25.8 g of first crude (±) -Δ ⁹ -THC m-nitrobenzenesulfonate residue. Analysis (HPLC) of the first crude (±) -Δ ⁹ -THC m-nitrobenzenesulfonate residue indicated that it had a purity of 42.9 wt%.

The first crude (±) -Δ ⁹ -THC m-nitrobenzenesulfonate residue was dissolved in isopropanol (95 mL) at 50 ° C. The obtained solution was cooled to room temperature, powdery crystalline (±) -Δ ⁹ -THC m-nitrobenzenesulfonate was added as a seed crystal, cooled to 0 ° C., and stirred at 0 ° C. for 12 hours. The resulting mixture was filtered and the resulting solid was cooled to heptane (
65 mL). The solids were then dried under reduced pressure to give 10.3 g of the second crude (±) -Δ ⁹ -THC m-nitrobenzenesulfonate residue as a yellow solid. Analysis of the second crude (±) -Δ ⁹ -THC m-nitrobenzenesulfonate residue (
HPLC) showed it to have a purity of 79.1%.

The second crude (±) -Δ ⁹ -THC m-nitrobenzenesulfonate (10.0 g) was dissolved in dichloromethane (13 mL), and the resulting solution was added to a 10 cm Vigreux column (V
igreux column) and a distillation pot equipped with an addition port. Thereafter, the contents of the distillation pot were distilled, during which time isopropanol (40 mL) was continuously added dropwise to the mixture through the addition port. The distillation was stopped when the vapor temperature at the column head reached 82.4 ° C. The contents of the distillation pot were cooled therein from 0 ° C. to 5 ° C., and the resulting suspension was stirred at 0 ° C. to about 5 ° C. for 12 hours. The suspension was filtered and the resulting solid was washed with cold heptane (22 mL). The solids were then dried under reduced pressure to give crystalline (±) -Δ ⁹ -THC m-nitrobenzenesulfonate. Yield: 7.0 g, 59%
. Analysis of the product (HPLC) showed it to have a purity of 99.0%.

  Melting point: 105-107 ° C.

X-ray powder diffraction pattern: about 9.3, 10.6, 12.5, 15.2, 18.7, 19.3, 2
Characteristic peak represented by diffraction angle 2θ observed at 1.2 and 22.9.

(±) -Δ ⁹ -THC Preparation of Crystalline (±) -Δ ⁹ -THC m- nitrobenzenesulfonate (4.5g, 7.5mmol), a mixture of 50% NaOH (5.3g) and methanol (110 mL) Was stirred at 50 ° C. for about 1-2 hours and then cooled to room temperature. The cooled mixture is then treated with cold water (1 × 150 mL), after which the pH is about 7
Treated with 10% HCl until. The resulting mixture was extracted with heptane (3 × 75 mL) and the combined organic extracts were washed with 7% NaHCO ₃ (100 mL) and water (100 mL). The organic phase was dried over Na ₂ SO ₄ and filtered. The resulting filtrate was then concentrated under reduced pressure to yield 2.5 g of crude (±) -Δ ⁹ -THC. Analysis of the crude product (HPLC)
Showed that it contained 92.6% by weight of (±) -Δ ⁹ -THC.

The crude (±) -Δ ⁹ -THC was dissolved in heptane (5 mL) at 40 ° C. The resulting solution was cooled to 0 ° C., and powdered crystalline (±) -Δ ⁹ -THC was added as a seed crystal for 12 hours.
Stir at -15 ° C. The resulting mixture was filtered and the resulting solid was cooled to heptane (3.5 mL).
). The solids were then dried under reduced pressure to give (±) -Δ ⁹ -THC as off-white crystals. Yield: 2.1 g, 74%. Its crystallinity (±) -Δ ⁹ -TH
C was stable at 25 ° C. under air and laboratory lighting. Analysis of the product (H
PLC) showed it to have a purity of 99.0%. The analytical sample recrystallized from hexane had a melting point of 65-66 ° C.

Optical rotation: [α] _D ²⁰ 0.0 ° (c = 0.53, CHCl ₃ ).

¹ H NMR: The product spectrum was consistent with the structure.

5.18. Preparation of (±) -Δ ⁹ -THC from trans-(−)-Δ ⁹ -THC and trans-(+)-Δ ⁹ -THC Trans-(−)-Δ ⁹ -THC (1a) (10 g; 93 9. Based on a purity of 5%
35 g of trans-(−)-Δ ⁹ -THC), trans-(+)-Δ ⁹ − from Example 11.
A solution of THC (1b) (17.0 g; 8.36 g based on 49.2% purity) and heptane (28 mL) was cooled to 0 ° C. and (±) -Δ ⁹ -THC (0.02 g) was It was put as a seed crystal and stirred at 0 ° C. for 5 hours. The resulting mixture was cooled to −15 ° C. and stirred for an additional 48 hours at −15 ° C. The mixture was filtered and the resulting solid was cooled n-heptane (4 mL).
Washed with. Then, under reduced pressure The solids were dried at 35 ° C., the crude (±) -Δ ⁹ -
THC was obtained. Yield: 11.4 g, 68%. Analysis of the crude (±) -Δ ⁹ -THC (HP
LC) showed it to have a purity of 93.6%.

The crude (±) -Δ ⁹ -THC (11.2 g) was dissolved in heptane (15 g) at 50 ° C. and the mixture was cooled to 0 ° C. with stirring. The resulting mixture was stirred at 0 ° C. for 2 hours,
The mixture was cooled to 15 ° C. and further stirred at −15 ° C. for 48 hours. The mixture was filtered and the resulting crystalline solid was washed with cold n-heptane (4 mL). The solids are then removed under reduced pressure and 3
Drying at 5 ° C. gave crystalline (±) -Δ ⁹ -THC. Yield: 9.2 g, 82%. Analysis of its crystalline (±) -Δ ⁹ -THC (HPLC) showed it to be 97.7% pure.

Preparation of crystalline (±) -Δ ⁹ -THC (+)-Δ ⁹ -THC (2.70 g; 2.55 g trans-(+)-Δ ⁹ -THC) based on 94.3% purity ( Crystalline (±) -Δ ⁹ -THC obtained from enantioselective chromatography as described in Example 21) and trans- (from Example 9)
-)-Δ ⁹ -THC (3.36 g; 2.76 g of trans- based on 82.2% purity)
(−)-Δ ⁹ -THC) was dissolved in heptane (9.5 mL). The resulting solution was cooled to 0 ° C., and crystalline (±) -Δ ⁹ -THC (0.01 g) was added as a seed crystal. The resulting mixture was stirred for 5 hours at 0 ° C. and for 72 hours at −15 ° C. The resulting mixture is filtered,
The resulting solid was washed with cold heptane (8 mL). The solids were then removed under reduced pressure and 35
Drying at 0 ° C. gave crystalline (±) -Δ ⁹ -THC. Yield: 4.4 g, 79.7%. Analysis of the product (HPLC) showed it to be 98.7% pure.

5.20. Preparation of crystalline (±) -Δ ⁹ -THC Crude trans-(−)-Δ ⁹ was prepared by the process described in Examples 9 and 11, respectively.
-THC and crude trans-(+)-Δ ⁹ -THC were prepared. Crude trans-(−)-Δ ⁹ -THC (27.7 g; 10.0 g trans-(−) — in 65 mL heptane
Δ ⁹ -THC) and crude trans-(+)-Δ ⁹ -THC (24.3 g; 10.0
g of trans-(+)-Δ ⁹ -THC), 50% and heptane (315 mL), 50% caustic (33 g), water (16.5 mL) and methanol (1
90 mL) with methanol-caustic solution for 20 minutes at 25 ° C.
The resulting purple methanol-caustic (lower) phase is recovered and the organic phase is washed with a methanol-caustic solution containing 50% caustic (33 g), water (16.5 mL) and methanol (190 mL); Remixed at 25 ° C. for 20 minutes. The resulting methanol-caustic phase was recovered and the combined methanol-caustic phase was taken up with 10% of citric acid in water.
Treat slowly with solution (545 g). The resulting yellow mixture was then heptane (
200 g). The resulting organic phase was collected and washed with water (150 mL) and Na ₂ S
Dried over O ₄ and filtered. The resulting filtrate was dried by azeotropic distillation and concentrated under reduced pressure. The resulting red oil (41.76 g) was dissolved in heptane (57 g) and cooled to 0 ° C.
100 mg of crystalline (±) -Δ ⁹ -THC was seeded. The resulting mixture is -1
The mixture was cooled to 5 ° C and stirred at -15 ° C for 12 hours. The resulting mixture was filtered with suction and the solid was washed with cold heptane (3 × 10 mL). The resulting yellow solid was allowed to dry with suction, yielding 12.45 g of crude (±) -Δ ⁹ -THC.

The crude (±) -Δ ⁹ -THC (12.45 g) was dissolved in 50 ° C. heptane (25 mL) and the resulting solution was cooled to −10 ° C. for 2-3 hours. The resulting mixture is filtered with suction,
The solid was washed 3 times with cold heptane (10, 10 and 20 mL). The solids were then left to dry with suction to give (±) -Δ ⁹ -THC as white crystals.
Yield: 8.70 g; Yield 14% (based on olivetol); 44% yield based on (−)-Δ ⁹ -THC and (+)-Δ ⁹ -THC. Analysis of its crystallinity (±) -Δ ⁹ -THC (HP
LC) showed it to have a purity of 96.45%.

5.21. (±) - [delta ⁹ transformer from ^{-THC - (-) - Δ 9} -THC and trans - (+) - Δ ⁹ as -THC split stationary phase Chiralpak (R) AD (TM) 20 [mu] m chiral (Japan,
Daicel Chemical Industries, Ltd. in Tokyo) (load capacity 500 mg per injection, UV at 228 nm) and n-heptane: 2-propanol (95: 5 (v: v)) as the mobile phase at 20 ° C. to 25 ° C. Merck column (210 x 5) used at a flow rate of 200 mL / min
(±) -Δ ⁹ -THC (2.00 g) by flash chromatography at 0 mm).
, Purity 97.7%). Fractions in which only trans-(−)-Δ ⁹ -THC was observed were combined and volatile components were removed using a rotary evaporator at 35 ° C. to 40 ° C.,
Trans-(−)-Δ ⁹ -THC (1a) was obtained. Yield: 0.89 g; 89%. Analysis of the product (HPLC) showed it to be at least 99.9% pure, ie no other cannabinoids were detected.

5.22. (±) -Δ ⁹ transformer from ^{-THC - (-) - Δ 9} -THC and trans - (+) - Δ ⁹ -THC Crystalline from dividing Example 15 (±) -Δ ⁹ -THC (3 8 g) with 8 mL heptane: 2-
Dissolved in a propanol (95: 5 (v: v)) mixture. The resulting solution is called Chiral
pak® AD chiral derivatized silica (Ch, Exton, PA)
iral Technologies Inc. 2 inch stainless steel filled with
It was injected into the “Load and Lock” column (Varian). Elution was performed under isocratic conditions with a solution of heptane: isopropanol (95: 5 (v: v)) at a temperature of about 25 ° C. and a flow rate of 250 mL of eluent / min. Detection of the compound in the eluate was performed by UV absorption at 235 nm.

The trans-(+)-Δ ⁹ -THC elutes first and the combined trans-(+)-Δ ⁹ -TH
The C eluate was concentrated under reduced pressure to give 1.5 g of trans-(+)-Δ ⁹ -THC (1b) as a reddish yellow oil.

Trans-(−)-Δ ⁹ -THC elutes after trans-(+)-Δ ⁹ -THC, and the combined trans-(−)-Δ ⁹ -THC eluate is concentrated under reduced pressure, − (−) − Δ ⁹
-THC (1a) was obtained as a thick, thick reddish yellow oil. Yield: 1.4g.
Analysis (HPLC) of the trans-(−)-Δ ⁹ -THC product showed it to be 99.4% pure.

23.3. (±) -Δ ⁹ transformer from ^{-THC - (-) - Δ 9} -THC and trans - (+) - Δ ⁹ -THC Crystalline from dividing Example 13 (±) -Δ ⁹ -THC (about About 26 mL of 95: 5
Dissolved in a heptane: IPA (v: v) mixture to give a 10 wt% solution. A portion (approximately 5 g) of the 10% solution was injected into a 220 × 50 mm stainless steel column (Merck) packed with Chiralpak® AD 20 μm chiral derivatized silica (Daicel Chemical Industries, Tokyo, Japan). Elution is isocratic under heptane: 2
A solution of propanol (95: 5 (v: v)) solvent, at about 25 ° C. and at a flow rate of 200 mL eluent / min. Detection of the product in the eluate was performed by UV absorption at 228 nm. Elution of the remaining portion of the 10% solution was performed as described above using approximately 3 × 5 g samples.

Fractions containing (+)-Δ ⁹ -THC were combined and concentrated under reduced pressure to give (+)-Δ ⁹ -THC.
Was obtained as a reddish yellow oil. Yield: 1.0 g. The analysis (HPLC) of the oil is
It was shown to have a purity of 97.0%.

Fractions containing trans-(−)-Δ ⁹ -THC were combined and concentrated under reduced pressure to give trans-(−)-Δ ⁹ -THC (1a) a thick, viscous reddish color. Obtained as a yellow oil. Yield: 1.0 g. Analysis of the product (HPLC) showed it to be 99.9% pure.

  The product was stored in a freezer and protected from light and oxygen.

The scope of the invention is not limited by the specific embodiments disclosed in the above examples, which are intended to illustrate some aspects of the invention, and any embodiment that is functionally equivalent may be Within range. Indeed, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art. They should be construed as falling within the scope of the appended claims.

A number of references have been cited, the entire disclosures of which are incorporated herein by reference.

Claims (30)

A method for removing impurities from a composition containing trans-(−)-Δ ⁹ -tetrahydrocannabinol and trans-(+)-Δ ⁹ -tetrahydrocannabinol,
(A) containing (i) a first organic phase containing a nonpolar organic solvent, and (ii) the trans-(−)-Δ ⁹ -tetrahydrocannabinol and the trans-(+)-Δ ⁹ -tetrahydrocannabinol Forming a two-phase composition comprising an alcohol-caustic phase to
(B) separating the alcohol-caustic phase containing the trans-(−)-Δ ⁹ -tetrahydrocannabinol and the trans-(+)-Δ ⁹ -tetrahydrocannabinol from the first organic phase. And (c) reacting the alcohol-caustic phase with an acid to form an acid-treated alcohol phase. (D) contacting the acid-treated alcohol phase with a second water-immiscible organic solvent, and (i) trans-(−)-Δ ⁹ Tetrahydrocannabinol and said trans-(+)-Δ ⁹ The removal method according to claim 1, further comprising the step of forming a second organic phase comprising tetrahydrocannabinol and (ii) an acid-treated alcohol phase. The removal method according to claim 2, further comprising (e) separating the second organic phase from the acid-treated alcohol phase. A method for removing impurities from a composition containing trans-(−)-Δ ⁹ -tetrahydrocannabinol or trans-(+)-Δ ⁹ -tetrahydrocannabinol,
(A) containing (i) a first organic phase containing a nonpolar organic solvent, and (ii) the trans-(−)-Δ ⁹ -tetrahydrocannabinol or the trans-(+)-Δ ⁹ -tetrahydrocannabinol Forming a two-phase composition comprising an alcohol-caustic phase to
(B) separating the alcohol-caustic phase containing the trans-(−)-Δ ⁹ -tetrahydrocannabinol or the trans-(+)-Δ ⁹ -tetrahydrocannabinol from the first organic phase. And (c) reacting the alcohol-caustic phase with an acid to form an acid-treated alcohol phase. (D) contacting the acid-treated alcohol phase with a second water-immiscible organic solvent, and (i) trans-(−)-Δ ⁹ -Tetrahydrocannabinol or said trans-(+)-Δ ⁹ 5. The removal method of claim 4, further comprising the step of forming a second organic phase comprising tetrahydrocannabinol and (ii) an acid treated alcohol phase. The removal method according to claim 5, further comprising (e) separating the second organic phase from the acid-treated alcohol phase. The removal method according to any one of claims 1 to 6 , wherein the acid is citric acid or acetic acid. The removal method according to any one of claims 1 to 7 , wherein the acid is added in an amount sufficient to achieve a pH of 5 to 9. From a first composition comprising trans-(−)-Δ ⁹ -tetrahydrocannabinol, trans-(+)-Δ ⁹ -tetrahydrocannabinol and a non-polar organic solvent, trans-(−)-Δ ⁹ -tetrahydrocannabinol Crystallizing (±) -Δ ⁹ -tetrahydrocannabinol, comprising crystallizing and trans-(+)-Δ ⁹ -tetrahydrocannabinol to yield crystalline (±) -Δ ⁹ -tetrahydrocannabinol. A manufacturing method of
The first composition is
(A) performing the method according to any of claims 1 to 3 ;
(B) From the obtained phase containing trans-(−)-Δ ⁹ -tetrahydrocannabinol and trans-(+)-Δ ⁹ -tetrahydrocannabinol, trans-(−)-Δ ⁹ -tetrahydrocannabinol cyclohexanol and the trans - (+) - delta ⁹ - step separating tetrahydrocannabinol; the transformer and from step (c) (b) - (-) - delta ⁹ - tetrahydrocannabinol and the trans - (+) The said manufacturing method which is obtained by the step which makes-(DELTA) ⁹ -tetrahydrocannabinol and nonpolar organic solvents contact, and forms a 1st composition. Trans-(-)-Δ ⁹ -Tetrahydrocannabinol, trans-(+)-Δ ⁹ From a first composition comprising tetrahydrocannabinol and a non-polar organic solvent, trans-(−)-Δ ⁹ -Tetrahydrocannabinol and trans-(+)-Δ ⁹ -Tetrahydrocannabinol is crystallized and crystallinity (±)-Δ ⁹ Crystallinity (±) -Δ comprising producing tetrahydrocannabinol ⁹ A process for producing tetrahydrocannabinol, comprising:
  The first composition is
  (A) performing the method according to any of claims 4 to 6;
  (B) The obtained trans-(-)-Δ ⁹ -Tetrahydrocannabinol or said trans-(+)-Δ ⁹ The trans-(−)-Δ from the phase containing tetrahydrocannabinol ⁹ -Tetrahydrocannabinol or said trans-(+)-Δ ⁹ Separating the tetrahydrocannabinol; and
  (C) said trans-(−)-Δ from step (b) ⁹ -Tetrahydrocannabinol or said trans-(+)-Δ ⁹ -The said manufacturing method which is obtained by the step which makes a tetrahydrocannabinol and nonpolar organic solvent contact, and forms a 1st composition. In step (c), said from step (b) trans - (-) - Δ ⁹ - tetrahydrocannabinol or the trans - (+) - Δ ⁹ - enantiomer of tetrahydrocannabinol is added, in claim 10 The manufacturing method as described. From a first composition comprising trans-(−)-Δ ⁹ -tetrahydrocannabinol, trans-(+)-Δ ⁹ -tetrahydrocannabinol and a non-polar organic solvent, trans-(−)-Δ ⁹ -tetrahydrocannabinol Crystallizing (±) -Δ ⁹ -tetrahydrocannabinol, comprising crystallizing and trans-(+)-Δ ⁹ -tetrahydrocannabinol to yield crystalline (±) -Δ ⁹ -tetrahydrocannabinol. A manufacturing method of
The first composition is
(1) (−)-cis-p-menta-2,8-dien-1-ol is converted to trans-(+)-Δ ⁹ -tetrahydrocannabinol and (+)-cis-p-menta-2 , 8-dien-1-ol is converted to trans-(−)-Δ ⁹ -tetrahydrocannabinol;
(2) mixing the crude trans-(+)-Δ ⁹ -tetrahydrocannabinol obtained in step (1) and the crude trans-(−)-Δ ⁹ -tetrahydrocannabinol;
(3) forming a two-phase composition comprising (i) a first organic phase and (ii) an alcohol-caustic phase containing the mixture obtained in step (2);
(4) From the obtained phase containing trans-(−)-Δ ⁹ -tetrahydrocannabinol and trans-(+)-Δ ⁹ -tetrahydrocannabinol, the trans-(−)-Δ ⁹ -tetrahydrocannabinol cyclohexanol and the trans - (+) - delta ⁹ - step separating -tetrahydrocannabinol; and (5) the transformer from step (4) - (-) - delta ⁹ - tetrahydrocannabinol and the trans - (+) The said manufacturing method which is obtained by the step which makes-(DELTA) ⁹ -tetrahydrocannabinol and nonpolar organic solvents contact, and forms a 1st composition. (-)-Cis-p-menta-2,8-dien-1-ol is prepared from (-)-limonene oxide and (+)-cis-p-menta-2,8 is prepared from (+)-limonene oxide. The process according to claim 12 , further comprising the step of preparing -dien-1-ol. Step (1) is performed by reacting the cis -p- mentha-2,8-dien-1-ol and olivetol in the presence of an acid catalyst and a dehydrating agent, according to claim 12 or 13 Manufacturing method. The production method according to claim 14 , wherein the acid catalyst is p-toluenesulfonic acid. From a first composition comprising trans-(−)-Δ ⁹ -tetrahydrocannabinol, trans-(+)-Δ ⁹ -tetrahydrocannabinol and a non-polar organic solvent, trans-(−)-Δ ⁹ -tetrahydrocannabinol Crystallizing (±) -Δ ⁹ -tetrahydrocannabinol, comprising crystallizing and trans-(+)-Δ ⁹ -tetrahydrocannabinol to yield crystalline (±) -Δ ⁹ -tetrahydrocannabinol. A manufacturing method of
The first composition is
(1) reacting (−)-cannabidiol with a Lewis acid in an inert solvent under anhydrous conditions, and reacting (+)-cannabidiol with a Lewis acid in an inert solvent under anhydrous conditions;
(2) mixing the crude trans-(+)-Δ ⁹ -tetrahydrocannabinol obtained in step (1) and the crude trans-(−)-Δ ⁹ -tetrahydrocannabinol;
(3) forming a two-phase composition comprising (i) a first organic phase and (ii) an alcohol-caustic phase containing the mixture obtained in step (2);
(4) From the obtained phase containing trans-(−)-Δ ⁹ -tetrahydrocannabinol and trans-(+)-Δ ⁹ -tetrahydrocannabinol, the trans-(−)-Δ ⁹ -tetrahydrocannabinol (5) separating the trans-(+)-Δ ⁹ -tetrahydrocannabinol and (5) the trans-(−)-Δ ⁹ -tetrahydrocannabinol and trans-(+) from step (4 ) The said manufacturing method which is obtained by the step which makes-(DELTA) ⁹ -tetrahydrocannabinol and nonpolar organic solvents contact, and forms a 1st composition. Wherein the Lewis acid is BF ₃ · Et ₂ O, The method according to claim 16. From a first composition comprising trans-(−)-Δ ⁹ -tetrahydrocannabinol, trans-(+)-Δ ⁹ -tetrahydrocannabinol and a non-polar organic solvent, trans-(−)-Δ ⁹ -tetrahydrocannabinol Crystallizing (±) -Δ ⁹ -tetrahydrocannabinol, comprising crystallizing and trans-(+)-Δ ⁹ -tetrahydrocannabinol to yield crystalline (±) -Δ ⁹ -tetrahydrocannabinol. A manufacturing method of
The first composition is
(1) (−)-Δ ⁸ -tetrahydrocannabinol and HCl are reacted, followed by dehydrochlorination, and (+)-Δ ⁸ -tetrahydrocannabinol and HCl are reacted, followed by dechlorination Performing hydrogen,
(2) mixing the crude trans-(+)-Δ ⁹ -tetrahydrocannabinol obtained in step (1) and the crude trans-(−)-Δ ⁹ -tetrahydrocannabinol;
(3) forming a two-phase composition comprising (i) a first organic phase and (ii) an alcohol-caustic phase containing the mixture obtained in step (2);
(4) From the obtained phase containing trans-(−)-Δ ⁹ -tetrahydrocannabinol and trans-(+)-Δ ⁹ -tetrahydrocannabinol, the trans-(−)-Δ ⁹ -tetrahydrocannabinol (5) separating the trans-(+)-Δ ⁹ -tetrahydrocannabinol and (5) the trans-(−)-Δ ⁹ -tetrahydrocannabinol and trans-(+) from step (4 ) The said manufacturing method which is obtained by the step which makes-(DELTA) ⁹ -tetrahydrocannabinol and nonpolar organic solvents contact, and forms a 1st composition. Trans-(-comprising separating a composition comprising (±) -Δ ⁹ -tetrahydrocannabinol and an eluting solvent on a chiral stationary phase to provide a trans-(−)-Δ ⁹ -tetrahydrocannabinol composition. ) - [delta ⁹ - process for the preparation of tetrahydrocannabinol composition, or (±) -Δ ⁹ - by a composition comprising tetrahydrocannabinol and an eluting solvent to separate on a chiral stationary phase, trans - (+) - Δ ⁹ - A process for preparing a trans-(+)-Δ ⁹ -tetrahydrocannabinol composition comprising providing a tetrahydrocannabinol composition comprising:
The (±) -Δ ⁹ - tetrahydrocannabinol is, crystalline (±) -Δ ⁹ - obtained from tetrahydrocannabinol, the crystalline (±) -Δ ⁹ - one tetrahydrocannabinol from claims 9 18, The said method which is obtained by the method of crab. The trans-(−)-Δ ⁹ -tetrahydrocannabinol is present in the first composition at 0.75 to 1.25 molar equivalents per molar equivalent of trans-(+)-Δ ⁹ -tetrahydrocannabinol. 20. A method according to any one of claims 9 to 19 present. The trans-(−)-Δ ⁹ -tetrahydrocannabinol is present in the first composition at 0.9 to 1.1 molar equivalents per molar equivalent of trans-(+)-Δ ⁹ -tetrahydrocannabinol. 21. A method according to claim 20 present. The trans-(−)-Δ ⁹ -tetrahydrocannabinol is present in the first composition at 0.95 to 1.05 molar equivalents per molar equivalent of trans-(+)-Δ ⁹ -tetrahydrocannabinol. 21. A method according to claim 20 present. The trans - (-) - Δ ⁹ - tetrahydrocannabinol is trans - (+) - Δ ⁹ - molar equivalents per tetrahydrocannabinol, with 1 molar equivalent, present in the first composition, according to claim 20 The method described in 1. Said (±) -Δ ⁹ -tetrahydrocannabinol is at least 95% by weight of trans-(−)-Δ ⁹ -tetrahydrocannabinol and trans-(+)-Δ ⁹ -tetrahydrocannabinol, based on the total amount of cannabinoids. 24. A method according to any one of claims 9 to 23 comprising a knoll. Said (±) -Δ ⁹ -tetrahydrocannabinol is at least 98% by weight of trans-(−)-Δ ⁹ -tetrahydrocannabinol and trans-(+)-Δ ⁹ -tetrahydrocannabinol, based on the total amount of cannabinoids. 25. The method of claim 24 , comprising a knoll. Said (±) -Δ ⁹ -tetrahydrocannabinol is at least 99% by weight of trans-(−)-Δ ⁹ -tetrahydrocannabinol and trans-(+)-Δ ⁹ -tetrahydrocannabinol, based on the total amount of cannabinoids. 25. The method of claim 24 , comprising a knoll. The non-polar organic solvent is a linear or branched (C ₄ -C ₁₀ ) aliphatic hydrocarbon, (C ₄ -C ₁₀ ) alicyclic hydrocarbon, or a mixture of any of these. The method according to any one of 9 to 26 . 28. The method of claim 27 , wherein the linear or branched hydrocarbon is pentane, hexane, heptane, isooctane, or a mixture of any of these. 29. The method of claim 28 , wherein the straight or branched chain hydrocarbon is n-heptane. In a composition comprising trans-(−)-Δ ⁹ -tetrahydrocannabinol, trans-(+)-Δ ⁹ -tetrahydrocannabinol, a water-immiscible organic solvent, a water-miscible alcohol, water and an alkali metal hydroxide. Wherein the trans-(−)-Δ ⁹ -tetrahydrocannabinol is present at 0.75 to 1.25 molar equivalents per molar equivalent of trans-(+)-Δ ⁹ -tetrahydrocannabinol. object.